OXIDIZED LIPIDS AND TREATMENT OR PREVENTION OF INFLAMMATION OR INFECTIOUS DISEASE CAUSED BY CORONAVIRUS

INFECTION

RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Appl. No. 63/004,201, filed

April 2, 2020, and to U.S. Provisional Appl. No. 63/144,683, filed February 2, 2021, which are incorporated herein by reference in their entireties.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the electronically submitted sequence listing (Name:

3182_095PC02_Seqlisting_ST25.txt; Size: 77,451 bytes; and Date of Creation: March 31, 2021, filed herewith, is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

[0003] The present invention relates to methods of treating or preventing inflammation caused by a coronavirus infection with oxidized lipid compounds. The present invention also relates to methods of treating or preventing an infectious disease or symptom caused by a coronavirus infection with oxidized lipid compounds. The present invention also relates to kits comprising an oxidized phospholipid and instructions for administering the oxidized phospholipid to a subject having or suspected of having inflammation or an infectious disease or symptom caused by a coronavirus infection.

Background

[0004] Coronaviruses are positive-stranded RNA viruses with large genome sizes that are known to cause diseases in animals and in humans. Seven strains of human coronaviruses are known: human coronavirus 229E (HCoV-229E); human coronavirus OC43 (HCoV-OC43); severe acute respiratory syndrome coronavirus (SARS-CoV); human coronavirus NL63 (HCoV-NL63, New Haven coronavirus); human coronavirus HKU1; Middle East respiratory syndrome-related coronavirus (MERS-CoV, also known as novel coronavirus 2012 and HCoV-EMC); and severe acute respiratory syndrome coronavirus 2 (also known as SARS-CoV-2; 2019-nCoV; novel coronavirus 2019, or COVID-19).

[0005] In humans, coronaviruses cause respiratory tract infections that are typically mild, such as the common cold. But coronaviruses can also cause much more serious infections such as coronavirus-induced severe acute respiratory syndrome (SARS-CoV). Woo et al, Microbiol. Immunol. ¥9:899-908 (2005). Although in most cases SARS-CoV infections are mild, approximately 20% of patients experience severe viral pneumonia that can progress to acute respiratory distress syndrome (ARDS) and death. Wu et al., 2020. JAMA Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China; Channappanavar et al., 2016, Cell Host & Microbe 19:181-193.

[0006] Accumulating evidence suggests that ARDS is caused by a state of hyper- inflammation or "cytokine storm" in patients. Mehta etal., 2020. Lancet 395:P1033- 1034. More specifically, high levels of chemokines and cytokines, triggered by the host immune response to SARS-CoV, are believed to contribute to the progressive pulmonary infiltration of monocyte/macrophages (Nicholls et al, 2003. Lancet 361 : 1773-1778), polymorphonuclear leukocytes (Chen etal., 2004. Letter. J. Pathol. 203:729-731), and T cells (Jiang et al, 2005. Am. J. Respir. Crit. Care Med. 171:850-857) and to eventual diffuse alveolar damage and fibrosis (Lee etal, 2003. N. Engl. J. Med. 348:1986-1994). Mechanistically, a two-wave model is suggested to explain how cellular infiltration may lead to ARDS: (i) pulmonary epithelial cells infected by SARS-CoV produce high levels of CCL2/monocyte chemoattractant protein 1 (MCP-1) and CXCL8/interleukin-8 (IL-8) which recruit predominantly macrophages and neutrophils, and (ii) macrophages recruited by CCL-2/MCP-1 are activated by SARS-CoV and produce a set of chemokines that attract more monocytes and neutrophils as well as activated T cells. Yen et al, 2006. Journal of Virology . 80:2684-2693.

[0007] Toll-like receptors (TLRs), a family of receptors imperative for the innate immune response against microbial invasion, can be divided into two major subgroups based on their cellular localization. Plasma membrane-expressed TLRs include TLR-1, -2, -4, -5 and -6, whereas the intracellular TLRs are TLR-3, -7, -8 and -9. Blasius et al, 2010. Immunity 32:305-15; and Kawai etal, 2010. Nat Immunol 11:373-84. The interaction between TLRs and their cognate agonists instigates a cascade of signals. These events culminate in the secretion of proinflammatory cytokines, including interleukin IL-6 and tumor necrosis factor (TNF)-a, and of chemokines. Kawai etal ., Immunity 34:637-50. The acute IFN and inflammatory response against virus infections is mediated by cellular pattern-recognition receptors that recognize specific viral proteins or the virus genetic material. In the case of coronaviruses, it was shown that the pathogenesis of SARS-CoV infection is induced through binding of the viral RNA and possibly the S protein to TLR3 and TLR4, respectively. Totura etal. , 2015. Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection. mBio 6:e00638-15; and Li et al., 2020. J. Med. Virol. 92:424-432.

[0008] Lecinoxoids are compounds that are structurally and functionally similar to naturally occurring molecules, known as oxidized lipids, which have immune modulating anti-inflammatory proprieties. However, unlike the native compounds which are short lived, lecinoxoids are chemically designed towards increased stability and potency. Lecinoxoids have dual anti-inflammatory activity: (i) inhibition of TLR4 and TLR2 pro- inflammatory pathways, and (ii) inhibition of monocyte chemotaxis, in a chemokine- agnostic manner. Mendel etal., Clin. Exp. Immunol. 2014. 175:126-137; Mendel etal., Dig. Dis. Sci. 2016. 61:2545-2553; Feige et al., Atherosclerosis. 2013. 229:430-439; and Yacov etal., Basic Clin. Pharmacol. Toxicol. 2019. 124:131-143.

[0009] This family of compounds includes l-hexadecyl-2-(4'-carboxybutyl)-glycero-3- phosphocholine (also known as VB-201 or CI-101). VB-201 demonstrates dual anti inflammatory activity: (i) inhibition of TLR4 and TLR2 pro-inflammatory pathways, and (ii) inhibition of monocyte chemotaxis, in a chemokine-agnostic manner. Mendel etal., 2014. Clin. Exp. Immunol. 175:126-37; Feige etal., 2013. Atherosclerosis 229:430-9.

[0010] VB-201 has been shown to suppress disease progression in animal models of atherosclerosis (Mendel et al., 2014. Clin. Exp. Immunol. 175:126-37; Feige et al, 2013. Atherosclerosis 229:430-9) and experimental autoimmune encephalitis (Mendel etal, 2010. J. Neuroimmunol . 226:126-35), in which activation and recruitment of monocytes are central for disease pathogenesis (Lei et al, 2011. Arterioscler. Thromb. Vase. Biol. 31:1506-16; King et al, 2009. Blood 113:3190-7; Yamasaki et al, 2014. J. Exp. Med.

211 : 1533-49. In addition, VB-201 treatment profoundly attenuated nonalcoholic steatohepatitis and liver fibrosis (Mendel etal ., 2016. Dig. Dis. Sci. 61:2545-53) and focal and segmental glomerulosclerosis development (Yacov et al ., 2019. Basic Clin. Pharmacol. Toxicol. 124:131-143), two fibrotic scarring diseases of the liver and kidneys respectively, which involves monocyte activation and accumulation in the affected tissue.

[0011] In March 2020, the World Health Organization declared the outbreak of COVID-

19 a pandemic. Like the severe acute respiratory syndrome (SARS) outbreak of 2003, and the Middle East respiratory syndrome (MERS) outbreaks of 2012, 2015, and 2018, COVID-19 has caused serious illness and death around the world. Likewise, in cats there are eight coronavirus strains whose infections can be associated with severe pneumonitis and peritonitis potentially associated with ascites. In addition, dogs can contract certain types of coronaviruses, such as canine respiratory coronavirus or canine coronavirus disease (CCoV).

[0012] There exists a need for therapies to treat and prevent coronavirus infection and to treat and prevent inflammation associated with a coronavirus infection.

BRIEF SUMMARY OF THE INVENTION

[0013] In one aspect, the present invention is directed to a method of treating or preventing inflammation caused by a coronavirus infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to Formula 1 :

Formula 1 wherein: n is an integer from 1 to 6, wherein when n is 1, Cn, Bn, Rn, and Y are absent, and Ci is attached to R'n; each of Bi, B2, ...Bn-1 and Bn is independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus and silicon, whereby each of said nitrogen, phosphorus and silicon is substituted by at least one substituent selected from the group consisting of hydrogen, lone pair electrons, alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy and oxo; each of Ai, A2, ... An-1 and An is independently selected from the group consisting of CR"R", C=0 and C=S,

Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-biphosphonate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl- phosphoethanolamine, phosphoglycerol and a moiety having the general formula: wherein: each of B' and B" is independently selected from the group consisting of sulfur and oxygen; and each of D' and D" is independently selected from the group consisting of hydrogen, alkyl, amino substituted alkyl, cycloalkyl, phosphonate and thiophosphonate; and each of Xi, X2, ...Xn-1 is independently a saturated or unsaturated hydrocarbon having the general Formula 2: Formula 2 wherein m is an integer from 1 to 26; and Z is selected from the group consisting of: wherein W is selected from the group consisting of oxygen and sulfur; wherein at least one of Xi, X2, ...Xn-1 comprises a Z other than hydrogen, and wherein: each of Ri, Ri, R2, ... Rn-1, Rn, R'n, each of R" and R" and each of Ra, R'a, Rb, R'b, ...Rm-1, R'm-1, Rm and R'm is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O- carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, or, alternatively, at least two of Ri, Ri, R2, ...Rn-1, Rn and R'n and/or at least two of Ra, R'a, Rb, R'b, ...Rm-1, R'm-1, Rm and R'm form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring.

[0014] In another aspect, the present invention is directed to a method of treating or preventing an infectious disease or symptom caused by a coronavirus infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to Formula 1: Formula 1 wherein: n is an integer from 1 to 6, wherein when n is 1, Cn, Bn, Rn, and Y are absent, and Ci is attached to R'n; each of Bi, B2, ...Bn-1 and Bn is independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus and silicon, whereby each of said nitrogen, phosphorus and silicon is substituted by at least one substituent selected from the group consisting of hydrogen, lone pair electrons, alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy and oxo; each of Ai, A2, ... An-1 and An is independently selected from the group consisting of CR"R", C=0 and C=S,

Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-biphosphonate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl- phosphoethanolamine, phosphoglycerol and a moiety having the general formula: wherein: each of B' and B" is independently selected from the group consisting of sulfur and oxygen; and each of D' and D" is independently selected from the group consisting of hydrogen, alkyl, amino substituted alkyl, cycloalkyl, phosphonate and thiophosphonate; and each of Xi, X2, ...Xn-1 is independently a saturated or unsaturated hydrocarbon having the general Formula 2: wherein m is an integer from 1 to 26; and Z is selected from the group consisting of: and -OR wherein W is selected from the group consisting of oxygen and sulfur; wherein at least one of Xi, X2, ...Xn-1 comprises a Z other than hydrogen, and wherein: each of Ri, Ri, R2, ... Rn-1, Rn, R'n, each of R" and R" and each of Ra, R'a, Rb, R'b, ...Rm-1, R'm-1, Rm and R'm is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O- carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, or, alternatively, at least two of Ri, Ri, R2, ...Rn-1, Rn and R'n and/or at least two of Ra, R'a, Rb, R'b, ...Rm-1, R'm-1, Rm and R'm form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring.

[0015] In one aspect, the present invention is directed to a method of treating or preventing inflammation caused by a coronavirus infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to Formula 5,

Formula 5 wherein each of Bi, B2, and B3 is independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus, and silicon; wherein each of said nitrogen, phosphorus and silicon is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy, and oxo; wherein R ¹⁰ is a C2-28 alkyl optionally substituted by one to five R ¹¹ substituents, wherein each R ¹¹ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy, and amino; wherein p is an integer selected from 1-10; wherein q is an integer selected from 1-26; wherein R ²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; and wherein Het is a heteroalicyclic ring or a heteroaryl.

[0016] In one aspect, the present invention is directed to a method of treating or preventing an infectious disease or symptom caused by a coronavirus infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a structure according to Formula 5, Formula 5 wherein each of Bi, B2, and B3 is independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus, and silicon; wherein each of said nitrogen, phosphorus and silicon is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy, and oxo; wherein R ¹⁰ is a C2-28 alkyl optionally substituted by one to five R ¹¹ substituents, wherein each R ¹¹ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy, and amino; wherein p is an integer selected from 1-10; wherein q is an integer selected from 1-26; wherein R ²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; and wherein Het is a heteroalicyclic ring or a heteroaryl.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Before explaining aspects of the invention in detail, it is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other aspects or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting. [0018] The present disclosure is directed to methods of treating or preventing inflammation associated with a coronavirus infection with an oxidized lipid compound (e.g., VB-201). The present disclosure is also directed to methods of treating or preventing a coronavirus infection with oxidized lipid compounds (e.g., VB-201). The present disclosure is also directed to methods of treating or preventing an infectious disease or symptom caused by a coronavirus infection with oxidized lipid compounds (e.g., VB-201).

Definitions

[0019] The terms "comprises", "comprising", "includes", "including", "having", and their conjugates mean "including but not limited to."

[0020] As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

[0021] Furthermore, "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0022] As used herein, the term "about" modifying an amount related to the invention refers to variation in the numerical quantity that can occur, for example, through routine testing and handling; through inadvertent error in such testing and handling; through differences in the manufacture, source, or purity of ingredients employed in the invention; and the like. Whether or not modified by the term "about", the claims include equivalents of the recited quantities. In one aspect, the term "about" means within 10% of the reported numerical value.

[0023] As used herein, the terms "treat," "treating," "treatment," and the like, refer to eliminating, reducing, or ameliorating inflammation, an infectious disease caused by a coronavirus infection, and/or a symptom caused by a coronavirus infection.

[0024] Symptoms of a coronavirus infection include, but are not limited to, fever, chills, cough, sore throat, congestion or runny nose, shortness of breath, dyspnea, diarrhea, loss of smell, loss of taste, nausea or vomiting, fatigue, muscle or body aches, headache, dizziness, malaise, muscle pain, chest pain or pressure, disorientation, exhaustion, evidence of lower respiratory disease ( e.g ., by clinical assessment or abnormal chest imaging), low oxygen saturation (e.g., SpCh <94% on room air at sea level and/or a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaCte/FiCte) <300 mmHg), high respiratory frequency (e.g., >30 breaths per minute), rapid heart rate (>90 beats per minute), high blood pressure (>120 mm Hg systolic and/or >80 mm Hg diastolic) presence of lung infiltrates (e.g., >50%), or a combination thereof..

[0025] As used herein, an "infectious disease caused by a coronavirus infection," or the like, includes, but is not limited to, pneumonia, hyper-inflammation, cytokine storm, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), middle east respiratory syndrome (MERS), sepsis, superinfection (i.e., increased susceptibility to other infections), common cold, bronchitis, or a combination thereof.

[0026] Although not precluded, treating inflammation or an infectious disease or symptom caused by a coronavirus infection does not require that the inflammation or infectious disease or symptom be completely eliminated. However, in one aspect, administration of an oxidized lipid (e.g, VB-201) leads to complete elimination of inflammation and/or an infectious disease or symptom caused by a coronavirus infection.

[0027] The term "human coronavirus" as used herein refers to a positive-stranded RNA virus that has a lipid envelope studded with club-shaped projections that infect humans, and mutated strains thereof. Sexton et al, Journal of Virology 90: 7415-7428 (2016).

[0028] The terms "HCoV-229E," "HCoV-OC43," "HCoV-NL63," "HCoV-HKUl,"

"SARS-CoV," "MERS-CoV," and "SARS-CoV-2" as used herein refer to the coronavirus pathogens known to infect humans. Lim et al, Diseases 2016, 4, 26; doi: 10.3390/diseases4030026; Lai et al, International Journal of Antimicrobial Agent 55:1-9 (2020).

[0029] The terms "severe acute respiratory syndrome" or "SARS" as used herein refers to the viral respiratory disease caused by SARS-CoV.

[0030] The term "Middle East Respiratory Syndrome" or "MERS" as used herein refers to the viral respiratory disease caused by MERS-CoV.

[0031] The term "Coronavirus Disease 2019" or "COVID-19" as used herein refers to the viral respiratory disease caused by SARS-CoV-2. [0032] As used herein throughout, the term "alkyl" refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. In some aspects, the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range; e.g ., "1-20", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom,

2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. In some aspects, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. In some aspects, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group can be substituted (e.g, with 1 to 5 substituent groups) or unsubstituted. In any of the aspects described herein, the alkyl can be unsubstituted. In any of the aspects described herein, the alkyl can also be substituted by one to five substituent groups, wherein the substituent group can be, for example, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfmyl, sulfonyl, cyano, nitro, azide, sulfonyl, sulfmyl, sulfonamide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino, as these terms are defined herein.

[0033] A "cycloalkyl" group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein one of more of the rings does not have a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane, cycloheptatriene, and adamantane. A cycloalkyl group can be substituted (e.g, with 1 to 5 substituent groups) or unsubstituted. In any of the aspects described herein, the cycloalkyl can be unsubstituted. In any of the aspects described herein, the cycloalkyl can also be substituted by one to five substituent groups, wherein the substituent group can be, for example, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfmyl, sulfonyl, cyano, nitro, azide, sulfonyl, sulfmyl, sulfonamide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino, as these terms are defined herein. [0034] An "alkenyl" group refers to an aliphatic hydrocarbon group which contains at least two carbon atoms and at least one carbon-carbon double bond, which can be straight or branched. An alkenyl group can be substituted or unsubstituted.

[0035] An "alkynyl" group refers to an aliphatic hydrocarbon group which contains at least two carbon atoms and at least one carbon-carbon triple bond. An alkynyl group can be substituted or unsubstituted.

[0036] An "aryl" group refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. In any of the aspects described herein, aryl groups can have 6 to 14 carbons, e.g ., 6 to 10 carbons. Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. The aryl group can be substituted (e.g, with 1 to 5 substituent groups) or unsubstituted. When substituted, the substituent group can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfmyl, sulfonyl, cyano, nitro, azide, sulfonyl, sulfmyl, sulfonamide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino, as these terms are defined herein. In any of the aspects described herein, the aryl group can be a phenyl group, optionally substituted, for example, by one to five substituent such as halogens (e.g, fluorine or chlorine), alkyl groups (e.g, a Ci-4 alkyl), or halogen substituted alkyls (e.g, trifluorom ethyl).

[0037] A "heteroaryl" group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi- electron system. In any of the aspects described herein, heteroaryl groups can have 5 to 14 ring atoms, e.g, 5 to 10 ring atoms (e.g, 5 or 6 ring atoms). Examples, without limitation, of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group can be substituted (e.g, with 1 to 5 substituent groups) or unsubstituted. When substituted, the substituent group can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfmyl, sulfonyl, cyano, nitro, azide, sulfonyl, sulfmyl, sulfonamide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino, as these terms are defined herein.

[0038] A "heteroalicyclic" group refers to a monocyclic or fused ring group having in the ring(s) one or more heteroatoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. In any of the aspects described herein, heteroalicyclic groups can have 3 to 10 ring atoms, e.g ., 5 to 10 ring atoms (e.g, 5 or 6 ring atoms). The heteroalicyclic can be substituted (e.g, with 1 to 5 substituent groups) or unsubstituted. When substituted, the substituted group can be, for example, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, halo, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, sulfmyl, sulfonyl, cyano, nitro, azide, sulfonyl, sulfmyl, sulfonamide, phosphonyl, phosphinyl, oxo, carbonyl, thiocarbonyl, urea, thiourea, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, sulfonamido, and amino, as these terms are defined herein. Representative examples are piperidine, piperazine, tetrahydrofuran, tetrahydropyran, morpholine and the like.

[0039] An "alkoxy" group refers to both an -O-alkyl and an -O-cycloalkyl group, wherein the alkyl or cycloalkyl can be any of those as defined herein.

[0040] An "aryloxy" group refers to both an -O-aryl and an -O-heteroaryl group, wherein the aryl or heteroaryl can be any of those as defined herein.

[0041] A "thiohydroxy" group refers to a -SH group.

[0042] A "thioalkoxy" group refers to both an -S-alkyl group, and an -S-cycloalkyl group, wherein the alkyl or cycloalkyl can be any of those as defined herein.

[0043] A "thioaryloxy" group refers to both an -S-aryl and an -S-heteroaryl group, wherein the aryl or heteroaryl can be any of those as defined herein.

[0044] A "carbonyl" group refers to a -C(=0)-R group, wherein R is hydrogen, alkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) or heteroalicyclic (bonded through a ring carbon) as defined herein.

[0045] An "aldehyde" group refers to a carbonyl group, wherein R is hydrogen.

[0046] A "thiocarbonyl" group refers to a -C(=S)-R group, wherein R is as defined herein. [0047] A "C-carboxy" group refers to a -C(=0)-0-R groups, wherein R is as defined herein.

[0048] An "O-carboxy" group refers to an RC(=0)-0- group, wherein R is as defined herein.

[0049] An "oxo" group refers to a =0 group.

[0050] A "carboxylic acid" group refers to a C-carboxyl group in which R is hydrogen.

[0051] A "halo" group or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0052] A "trihalom ethyl" group refers to a -CX3 group wherein X is a halo group as defined herein, e.g ., a CF3 group.

[0053] A "sulfmyl" group refers to an -S(=0)-R group, wherein R is as defined herein.

[0054] A "sulfonyl" group refers to an -S(=0)2-R group, wherein R is as defined herein.

[0055] An "S-sulfonamido" group refers to a -S(=0)2-NR2 group, with each of R as is defined herein.

[0056] An "N-sulfonamido" group refers to an RS(=0)2-NR group, wherein each of R is as defined herein.

[0057] An "O-carbamyl" group refers to an -OC(=0)-NR2 group, wherein each of R is as defined herein.

[0058] An "N-carbamyl" group refers to an ROC(=0)-NR- group, wherein each of R is as defined herein.

[0059] An "O-thiocarbamyl" group refers to an -OC(=S)-NR2 group, wherein each of R is as defined herein.

[0060] An "N-thiocarbamyl" group refers to an ROC(=S)NR- group, wherein each of R is as defined herein.

[0061] An "amino" group refers to an -NR2 group wherein each of R is as defined herein.

[0062] A "C-amido" group refers to a -C(=0)-NR2 group, wherein each of R is as defined herein.

[0063] An "N-amido" group refers to an RC(=0)-NR- group, wherein each of R is as defined herein.

[0064] A "urea" group refers to an -NRC(=0)-NR2 group, wherein each of R is as defined herein.

[0065] A "guanidino" group refers to an -RNC(=N)-NR2 group, wherein each of R is as defined herein. [0066] A "guanyl" group refers to an R2NC(=N)- group, wherein each of R is as defined herein.

[0067] The term "phosphonyl" or "phosphonate" describes a -P(=0)(OR)2 group, with R as defined herein.

[0068] The term "phosphate" describes an -0-P(=0)(0R)2 group, with each of R as defined herein.

[0069] A "phosphoric acid" is a phosphate group wherein each of R is hydrogen.

[0070] The term "phosphinyl" describes a -PR2 group, with each of R as defined herein.

[0071] The term "thiourea" describes a -NR-C(=S)-NR- group, with each of R as defined herein.

[0072] The term "saccharide" refers to one or more sugar units, either an open-chain sugar unit or a cyclic sugar unit ( e.g ., pyranose- or furanose-based units), and encompasses any monosaccharide, disaccharide and oligosaccharide, unless otherwise indicated.

[0073] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as | R - S | *100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as ([a]obs/[oc]max)* 100, where [oc] ₀ bs is the optical rotation of the mixture of enantiomers and [oc]max is the optical rotation of the pure enantiomer.

[0074] The term "salt" includes both internal salt or external salt. In some aspects, the salt is an internal salt, i.e., a zwitterion structure. In some aspects, the salt is an external salt. In some aspects, the external salt is a pharmaceutically acceptable salt having a suitable counter ion. Suitable counterions for pharmaceutical use are known in the art.

[0075] Throughout this application, various aspects of this invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range, such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5 and 6. This applies regardless of the breadth of the range.

Oxidized Lipids

[0076] The methods of the present invention are directed to administration of an oxidized lipid compound. In some aspects, an oxidized lipid on the invention is a compound having a structure according to Formula 1 :

Formula 1 or a pharmaceutically acceptable salt, a hydrate or a solvate thereof, wherein: n is an integer from 1 to 6, wherein when n is 1, Cn, Bn, Rn, and Y are absent, and Ci is attached to R'n; each of Bi, B2, ...Bn-1 and Bn is independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus and silicon, wherein each of said nitrogen, phosphorus and silicon is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy and oxo; each of Ai, A2, ... An-1 and An is independently selected from the group consisting of CR"R", C=0 and C=S,

Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5-biphosphonate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl- phosphoethanolamine, phosphoglycerol and a moiety having the general formula: wherein: each of B' and B" is independently selected from the group consisting of sulfur and oxygen; and each of D' and D" is independently selected from the group consisting of hydrogen, alkyl, amino substituted alkyl, cycloalkyl, phosphonate and thiophosphonate; and each of Xi, X2, ...Xn-1 is independently a saturated or unsaturated hydrocarbon having the general Formula 2:

Formula 2 wherein, m is an integer from 1 to 26; and

Z is selected from the group consisting of: wherein W is selected from the group consisting of oxygen and sulfur; wherein at least one of Xi, X2, ...Xn-1 comprises a Z other than hydrogen, and wherein: each of Ri, Ri, R2, ... Rn-1, Rn, R'n, each of R" and R" and each of Ra, R'a, Rb, R'b, ...Rm-1, R'm-1, Rm and R'm is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O- carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, or, alternatively, at least two of Ri, Ri, R2, ...Rn-1, Rn and R'n and/or at least two of Ra, R'a, Rb, R'b, ...Rm-1, R'm-1, Rm and R'm form at least one four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof.

[0077] In other aspects, an oxidized lipid on the invention is a compound having a structure according to Formula 3:

Formula 3 or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0078] In Formula 3, n is an integer selected from 1 to 4.

[0079] In Formula 3, Bi, each B2, and B3 are independently selected from the group consisting of oxygen, sulfur, and NR4, wherein R4 is selected from hydrogen, alkyl, cycloalkyl, aryl, and acyl.

[0080] In Formula 3, Ai and each A2 are independently selected from the group consisting of CReRee, CRe=CRee, C=0 and C=S, wherein Re and Ree are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl.

[0081] In Formula 3, Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4- phosphate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine- diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, phosphoglycerol, and a moiety having the general formula: wherein: each of B' and B" is independently selected from the group consisting of sulfur and oxygen; and

D' and D" are independently selected from the group consisting of hydrogen, alkyl, aminoalkyl, cycloalkyl, phosphonate and thiophosphonate.

[0082] In Formula 3, Xi and each X2 are independently a saturated or unsaturated, linear or branched hydrocarbon, wherein at least one of Xi and X2 is substituted with an oxidized moiety Z selected from the group consisting of: wherein W is oxygen or sulfur; and Rd and Rdd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl.

[0083] In one aspect in Formula 3, Xi and each X2 independently have the general Formula 4:

Formula 4

[0084] In Formula 4, m is an integer selected from 1 to 26.

[0085] In Formula 4, Z is selected from the group consisting of: , and OH, wherein W is oxygen or sulfur; and Rd and Rdd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, wherein at least one of Xi and X2 comprises a Z other than hydrogen.

[0086] In Formula 3 and Formula 4, Ri, Ri _a , each R2, R3, R3a, Ra, Raa, each Rb, each Rbb,

Rcand Rcc are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C- carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy and amino, wherein at least two of Ri, Ria, R2, R3 and R3a are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring, and wherein at least two of Ra, Raa, Rb, Rbb, Rc, and Rcc are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring.

[0087] In one aspect in Formula 3, n is 1 or 2. In another aspect in Formula 3, n is 1.

[0088] In one aspect in Formula 3, Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4- phosphate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine- diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, and phosphoglycerol.

[0089] In another aspect in Formula 3, Y is selected from the group consisting of hydrogen, phosphoryl choline, and phosphoryl ethanolamine.

[0090] In another aspect in Formula 3, Y is selected from the group consisting of phosphoryl choline, and phosphoryl ethanolamine.

[0091] In one aspect in Formula 3, Y is phosphoryl choline. [0092] In one aspect in Formula another aspect in Formula 3, Z is a carboxylic acid group.

[0093] In a further aspect in Formula 3, n is 1 and Y is phosphoryl choline.

[0094] In a further aspect in Formula 3, each of Bi, B2, and B3 is oxygen.

[0095] In a further aspect in Formula 3, n is 1, Y is phosphoryl choline, and each of Bi, B2, and B3 is oxygen.

[0096] In one aspect, the oxidized lipid useful in any of the methods of the present disclosure has a structure according to Formula 3a:

Formula 3a or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0097] In Formula 3a, Bi, B2, and B3 are independently selected from oxygen and sulfur.

[0098] In Formula 3a, Ai and A2 are independently selected from the group consisting of CH 2, CH=CH, C=0 and C=S.

[0099] In Formula 3a, Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4- phosphate, phosphoinositol-4,5-bisphosphate, pyrophosphate, phosphoethanolamine- diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, phosphoglycerol, and a moiety having the general formula: wherein: each of B' and B" is independently selected from the group consisting of sulfur and oxygen; and each of D' and D" is independently selected from the group consisting of hydrogen, alkyl, amino substituted alkyl, cycloalkyl, phosphonate and thiophosphonate.

[0100] In Formula 3a, Ri, Ria, R2, R3, and R _3a , are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S- thiocarboxy and amino, wherein at least two of Ri, Ria, R2, R3 and R3a are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring, and wherein at least two of Ra, Raa, Rb, Rbb, Rc, and Rcc are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring;

[0101] In Formula 3a, Xi and X2 are independently a saturated or unsaturated, linear or branched hydrocarbon, wherein at least one of Xi and X2 is substituted with an oxidized moiety Z having a formula selected from: wherein W is oxygen or sulfur; and Rd and Rdd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl.

[0102] In one aspect in Formula 3a, Xi and X2 independently have a structure according to Formula 4a: aa cc

Formula 4a

[0103] In Formula 4a, m is an integer selected from 1 to 26.

[0104] In Formula 4a, Ra, Raa, each Rb, each Rbb, Rc, and Rcc are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C- thiocarboxy, S-thiocarboxy and amino, wherein at least two of R _a , Raa, Rb, Rbb, Rc, and Rcc are optionally joined to form a four-, five- or six-membered aromatic, heteroaromatic, alicyclic or heteroalicyclic ring.

[0105] In Formula 4a, Z is selected from the group consisting of: wherein W is oxygen or sulfur; and Rd and Rdd are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, wherein at least one of Xi and X2 comprises a Z other than hydrogen.

OR,d

W=C

[0106] In one aspect in Formula 3a, Z is ' . In another aspect in Formula 3a, Z is a carboxylic acid group.

[0107] In one aspect in Formula 3a, Y is selected from the group consisting of hydrogen, acyl, alkyl, aryl, cycloalkyl, carboxy, saccharide, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N-glutaric acid, phosphoethanolamine-N-[methoxy(propylene glycol)], phosphoinositol-4- phosphate, phosphoinositol-4,5-bisphosphate, phosphoethanolamine-diethylenetriamine- pentaacetate, dinitrophenyl-phosphoethanolamine, and phosphoglycerol.

[0108] In one aspect in Formula 3a, Y is selected from the group consisting of hydrogen, phosphoryl choline, and phosphoryl ethanolamine.

[0109] In another aspect in Formula 3a, Y is selected from the group consisting of phosphoryl choline, and phosphoryl ethanolamine.

[0110] In one aspect in Formula 3a, Y is phosphoryl choline.

[0111] In a further aspect in Formula 3a, each of Bi, B2, and B3 is oxygen.

[0112] In a further aspect in Formula 3a, Y is phosphoryl choline, and each of Bi, B2, and

B3 is oxygen.

[0113] In one aspect in Formula 3a, the oxidized lipid has a structure according to

Formula 4b:

Formula 4b wherein Bi, B2, B3, Ai, A2, Xi, X2, and Y are defined as for Formula 3a.

[0114] In one aspect, each of Bi, B2, B3 in Formula 4b is oxygen and the oxidized lipid has a structure according to the Formula 4c:

Formula 4c

[0115] In Formula 4c, Ai is selected from the group consisting of CFh, CH=CH and

C=0. In one example, Ai in Formula 4c is CFh.

[0116] In Formula 4c, A2 is absent or CFh. [0117] In Formula 4c, Xi is an alkyl having from 1 to 30 carbon atoms.

[0118] In Formula wherein

E is absent or is an alkyl chain having from 1 to 24 carbon atoms;

F is selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, halide, acetoxy and aryl; and

Z is selected from the group consisting of: wherein R _d is selected from H, alkyl and aryl.

[0119] In Formula 4c, Y is selected from the group consisting of hydrogen, alkyl, aryl, phosphoric acid, phosphoryl choline, phosphoryl ethanolamine, phosphoryl serine, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl cardiolipin, phosphatidyl inositol, phosphoryl cardiolipin, phosphoryl inositol, ethylphosphocholine, phosphorylmethanol, phosphorylethanol, phosphorylpropanol, phosphorylbutanol, phosphorylethanolamine-N-lactose, phosphoethanolamine-N- [methoxy(propylene glycol)], phosphoinositol-4-phosphate, phosphoinositol-4,5- bisposphate, pyrophosphate, phosphoethanolamine-diethylenetriamine-pentaacetate, dinitrophenyl-phosphoethanolamine, phosphoglycerol and a moiety having the general formula: wherein: each of B ¹ and B" is independently selected from the group consisting of sulfur and oxygen; and each of D' and D" is independently selected from the group consisting of hydrogen, alkyl, amino substituted alkyl, cycloalkyl, phosphonate and thiophosphonate.

[0120] In one aspect in Formula 4c, Xi is alkyl having from 10 to 30 carbon atoms, or from 8 to 30 carbon atoms.

[0121] In one aspect in Formula 4c, E is alkyl having from 1 to 10 carbon atoms, or from

1 to 4 carbon atoms.

[0122] In one aspect in Formula 4c, Y is phosphoryl choline.

[0123] Each carbon atom in Formula 1, 2, 3, 3a, 4b and 4c is a chiral or non-chiral carbon atom, wherein each chiral carbon atom can have S-configuration or R-configuration.

[0124] In one aspect, the oxidized lipid is l-hexadecyl-2-(4'-carboxy)butyl-glycero-3- phosphocholine or l-hexadecyl-2-(4'-carboxybutyl)-glycero-3-phosphocholine. As used herein, l-hexadecyl-2-(4'-carboxy)butyl-glycero-3-phosphocholine and l-hexadecyl-2- (4'-carboxybutyl)-glycero-3-phosphocholine are the same and both refer to the same compound, VB-201. VB-201 according to aspects of this application may be a chiral enantiomer of l-hexadecyl-2-(4'-carboxybutyl)-glycero-3-phosphocholine, i.e., either the (R)- enantiomer ((R)-\ -hexadecyl-2-(4 ^, -carboxybutyl)-.sv/-glycero-3-phosphocholine) or the (S)- enantiomer ((S)-\ -hexadecyl-2-(4 ^, -carboxybutyl)-sn-glycero-3-phosphocholine), or a mixture thereof ( e.g ., a racemate). In one aspect, the oxidized lipid is (R)-\- hexadecyl-2-(4'-carboxy)butyl-sw-glycero-3-phosphocholine. In some aspects, the (R)- 1- hexadecyl-2-(4 ^, -carboxy)butyl-.sv/-glycero-3-phosphocholine has an enantiomeric purity of about 80% ee or more, e.g., about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In other aspects, the (R)-\ -hexadecyl-2-(4'- carboxy)butyl-.s//-glycero-3-phosphocholine has an enantiomeric purity of from about 80% ee to about 100% ee, about 85% ee to about 100% ee, about 90% ee to about 100% ee, about 95% ee to about 100%, about 80% ee to about 99.5% ee, about 85% ee to about 99.5% ee, about 90% ee to about 99.5% ee, about 95% ee to about 99.5%, or any range thereof.

[0125] In other aspects, the oxidized lipid has the following structure: [0126] In other aspects, the oxidized lipid has the following structure:

[0127] In another aspect, an oxidized lipid of the invention is a compound according to

Formula 5:

Formula 5 ^P wherein each of Bi, B2, and B3 is independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus and silicon, wherein each of said nitrogen, phosphorus and silicon is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, cycloalkyl, aryl, hydroxy, thiohydroxy, alkoxy, aryloxy, thioaryloxy, thioalkoxy and oxo; wherein R ¹⁰ is a C2-28 alkyl optionally substituted by one to five R ¹¹ substituents, wherein each R ¹¹ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C-carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy, and amino; wherein p is an integer selected from 1-10; wherein q is an integer selected from 1-26; wherein R ²⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl; and wherein Het is a heteroalicyclic ring or a heteroaryl. In other aspects, the oxidized lipid is a compound according to Formula 5, or a stereoisomer, a stereoisomeric mixture, or a salt thereof. In some aspects, the oxidized lipid having a structure according to Formula 5 has a zwittionic structure. In some aspects, the oxidized lipid is an external salt ( e.g ., a pharmaceutically acceptable salt) of the compound having a structure according to Formula 5. In some aspects, the compound according to Formula 5 has a structure according to Formula 5a or Formula 5b: V

V ^' † . Het H—Het

P P

Formula 5a Formula 5b or a salt thereof.

[0128] In some aspects, the compound has a structure according to Formula 5a, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g., about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In some aspects, the compound has a structure according to Formula 5b, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g, about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In other aspects, the compound has an enantiomeric purity of from about 80% ee to about 100% ee, about 85% ee to about 100% ee, about 90% ee to about 100% ee, about 95% ee to about 100%, about 80% ee to about 99.5% ee, about 85% ee to about 99.5% ee, about 90% ee to about 99.5% ee, about 95% ee to about 99.5%, or any range thereof.

[0129] Suitable Bi, B2, and B3 for Formula 5 are defined herein. In some aspects, Bi is

O. In some aspects, B2 is O. In some aspects, B3 is O. In some aspects, at least two of Bi, B2, and B3 are O, e.g ., Bi, B2 are O and B3 is O or S; Bi, B3 are O and B2 is O or S; or B2, B3 are O and Bi is O or S. In some aspects, Bi is S. In some aspects, B2 is S. In some aspects, B3 is S. In some aspects, at least two of Bi, B2, and B3 are S, e.g., Bi, B2 are S and B3 is O or S; Bi, B3 are S and B2 is O or S; or B2, B3 are S and Bi is O or S. In some aspects, all of Bi, B2, and B3 are O. In some aspects, all of Bi, B2, and B3 are S.

[0130] Suitable R ¹⁰ for Formula 5 are defined herein. In some aspects, R ¹⁰ is a C2-28 alkyl. In some aspects, R ¹⁰ is a straight chain C2-28 alkyl, e.g., an alkyl chain having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 carbons, substituted or unsubstituted. In some aspects, R ¹⁰ is a straight chain C2-28 alkyl, e.g., an alkyl chain having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 carbons, substituted by one to five R ¹¹ substituents, wherein each R ¹¹ is independently as defined herein, e.g, a halogen (e.g, F) or an alkyl (e.g, a Ci-10 alkyl). In some aspects, R ¹⁰ is selected from the group consisting of hexadecyl, dodecyl, octadecyl, octyl, eicosanyl, cis-9-hexadecenyl, (2'-octyl)dodecyl, and (15'- carboxy)pentadecyl. In some aspects, R ¹⁰ is hexadecyl. In some aspects, R ¹⁰ is (2'- octyl)dodecyl. In some aspects, R ¹⁰ is eicosanyl.

[0131] Suitable R ²⁰ for Formula 5 are defined herein. In some aspects, R ²⁰ is a hydrogen or an alkyl. In some aspects, R ²⁰ is hydrogen. In some aspects, R ²⁰ is an alkyl, e.g, a Ci- 4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl).

In some aspects, R ²⁰ is methyl.

[0132] Suitable values for p and q in Formula 5 are defined herein. In some aspects, q is an integer of 1-10, e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some aspects, q is 4. In some aspects, p is an integer of 1-7, e.g, 1, 2, 3, 4, 5, 6, or 7. In some aspects, p is 2.

[0133] Suitable Het for Formula 5 are defined herein. In some aspects, Het is a heteroaryl. In some aspects, Het is a monocyclic heteroaryl. In some aspects, Het is a nitrogen containing heteroaryl ( e.g ., monocyclic heteroaryl). In some aspects, Het is a monocyclic heteroaryl containing 1, 2, 3, or 4 nitrogen atoms. In some aspects, Het is a 6-member ring monocyclic heteroaryl, e.g., pyridine, pyrimidine, pyridazine, pyrazine, triazine, etc. In some aspects, Het is a 5-member ring monocyclic heteroaryl, e.g., imidazole, thiazole, isothiazole, oxazole, isoxazole, oxidiazole, pyrazole, triazole, etc. In some aspects, Het is a bicyclic heteroaryl containing nitrogen atoms, e.g., 1-3 nitrogen atoms, e.g., quinoline, isoquinoline, quinazoline, thienopyridine, thienopyrimidine, pyrrolopyridine, imidazopyridine, etc. In any of the aspects described herein, Het can be a nitrogen containing heteroaryl, wherein a nitrogen atom of the heteroaryl is directly connected to the alkylene chain, i.e., -(CH2)p- in Formula 5 to form a cation. In some aspects, Het is pyridine, wherein the nitrogen atom of the pyridine is directly connected to the alkylene chain, i.e., -(CH2)p- in Formula 5 form a pyridinium salt (e.g, an internal salt or an external salt as described herein). In some aspects, Het is an unsubstituted pyridine, wherein the nitrogen atom of the pyridine is directly connected to the alkylene chain, i.e., -(CH2) _p - in Formula 5. In some aspects, Het is a substituted pyridine, wherein the nitrogen atom of the pyridine is directly connected to the alkylene chain, i.e., -(CH2) _P - in Formula 5, wherein the pyridine is substituted by one to five (e.g, 1, 2, 3, 4, or 5) R ¹² substituents, wherein each R ¹² is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, halo, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, phosphonate, phosphate, phosphinyl, sulfonyl, sulfmyl, sulfonamide, amide, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, C- carbamate, N-carbamate, C-thiocarboxy, S-thiocarboxy, and amino as defined herein. In some aspects, each R ¹² is independently, e.g, a halogen (e.g., F, Cl), a C6-10 aryl (e.g., phenyl), a heteroaryl, or an alkyl (e.g., a Ci-io alkyl, e.g., a Ci-4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl). In some aspects, Het is a substituted pyridine and the pyridine is substituted by one R ¹² substituent at the 2-, 3-, or 4-position of the pyridine, wherein R ¹² is as defined herein, for example, a halogen (e.g, F, Cl), a phenyl, or a methyl.

[0134] In some aspects, an oxidized lipid of the invention is a compound having a structure according to Formula 6: Formula 6 or a stereoisomer, a stereoisomeric mixture, or a salt thereof. Suitable R ¹⁰ , R ²⁰ , p, q, and Het are those as defined herein for Formula 5. In some aspects, the oxidized lipid having a structure according to Formula 6 has a zwittionic structure. In some aspects, the oxidized lipid is an external salt ( e.g ., a pharmaceutically acceptable salt) of the compound having a structure according to Formula 6. In some aspects, the compound according to Formula 6 has a structure according to Formula 6a or Formula 6b:

Formula 6a Formula 6b or a salt thereof.

[0135] In some aspects, the compound is a S-isomer having a structure according to

Formula 6a, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g., about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In some aspects, the compound is a R-isomer having a structure according to Formula 6b, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g, about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In other aspects, the compound has an enantiomeric purity of from about 80% ee to about 100% ee, about 85% ee to about 100% ee, about 90% ee to about 100% ee, about 95% ee to about 100%, about 80% ee to about 99.5% ee, about 85% ee to about 99.5% ee, about 90% ee to about 99.5% ee, about 95% ee to about 99.5%, or any range thereof. [0136] In some aspects according to Formula 6, R ¹⁰ is selected from the group consisting of hexadecyl, dodecyl, octadecyl, octyl, eicosanyl, cis-9-hexadecenyl, (2'-octyl)dodecyl, and (15'-carboxy)pentadecyl; R ²⁰ is hydrogen or an alkyl, e.g, a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl); q is an integer of 1-

Het is an unsubstituted pyridine, wherein the nitrogen atom of the pyridine is directly connected to the alkylene chain, i.e., -(CFh in Formula 6, or Het is a substituted pyridine, wherein the nitrogen atom of the pyridine is directly connected to the alkylene chain, i.e., -(CFh in Formula 6, wherein the pyridine is substituted by one to five (e.g.,

1, 2, 3, 4, or 5) R ¹² substituents, wherein each R ¹² is independently as defined herein, e.g, a halogen (e.g, F, Cl), a C6-10 aryl (e.g, phenyl), a heteroaryl, or an alkyl (e.g, a Ci-io alkyl, e.g, a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl). In some aspects, Het is a substituted pyridine and the pyridine is substituted by one R ¹² substituent at the 2-, 3-, or 4-position of the pyridine, wherein R ¹² is as defined herein, for example, a halogen (e.g, F, Cl), a phenyl, or a methyl.

[0137] In some aspects, an oxidized lipid of the invention is a compound having a structure according to Formula 7: ormu a or a stereoisomer, a stereoisomeric mixture, or a salt thereof, wherein R ¹⁰ , R ¹² , R ²⁰ , p, and q are as defined herein for Formula 5. In some aspects, the oxidized lipid is a zwittionic structure according to Formula 7. In some aspects, the oxidized lipid is an external salt ( e.g ., a pharmaceutically acceptable salt) of the compound having a structure according to Formula 7. In some aspects, the oxidized lipid according to Formula 7 has a structure according to Formula 7a or Formula 7b: ormu a or a salt thereof.

[0138] In some aspects, the compound is a S-isomer having a structure according to

Formula 7a, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g, about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In some aspects, the compound is a R-isomer having a structure according to Formula 7b, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g. , about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In other aspects, the compound has an enantiomeric purity of from about 80% ee to about 100% ee, about 85% ee to about 100% ee, about 90% ee to about 100% ee, about 95% ee to about 100%, about 80% ee to about 99.5% ee, about 85% ee to about 99.5% ee, about 90% ee to about 99.5% ee, about 95% ee to about 99.5%, or any range thereof.

[0139] In some aspects according to Formula 7, R ¹⁰ is selected from the group consisting of hexadecyl, eicosanyl and (2'-octyl)dodecyl; R ²⁰ is hydrogen or a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl); q is an integer of 2-6, e.g, 2, 3, 4, 5, or 6; p is an integer of 2-5, e.g, 2, 3, 4, or 5; and the pyridine is substituted by 0 to 3 (e.g, 0, 1, 2, or 3) R ¹² substituents, wherein each R ¹² is independently as defined herein, e.g, a halogen (e.g, F, Cl), a C6-10 aryl (e.g, phenyl), a heteroaryl, or a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso butyl, tert-butyl). In some aspects, R ¹⁰ is selected from the group consisting of hexadecyl, eicosanyl and (2'-octyl)dodecyl; R ²⁰ is hydrogen or methyl; q is 2, 3, 4, 5, or 6; p is 2, 3, 4, or 5; and the pyridine is substituted by 0 to 3 (e.g, 0, 1, 2, or 3) R ¹² substituents, wherein each R ¹² is independently is a halogen (e.g, F, Cl), a C6-10 aryl (e.g, phenyl), a heteroaryl, or a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, iso-butyl, tert-butyl). In some aspects, R ¹⁰ is selected from the group consisting of hexadecyl, eicosanyl and (2'-octyl)dodecyl; R ²⁰ is hydrogen or methyl; q is 4; p is 2; and the pyridine is substituted by 0, 1, or 2 R ¹² substituents, wherein each R ¹² is independently a halogen ( e.g ., F, Cl), a phenyl, or a methyl. In some aspects according to Formulae 7, 7a, and 7b, R ¹⁰ is selected from the group consisting of hexadecyl, eicosanyl, and (2'-octyl)dodecyl. In some aspects according to Formulae 7, 7a, and 7b, R ²⁰ is a hydrogen or a Ci-4 alkyl. In some aspects according to Formulae 7, 7a, and 7b, q is an integer of 2-6. In some aspects according to Formulae 7, 7a, and 7b, p is an integer of 2- 5. In some aspects according to Formulae 7, 7a, and 7b, the pyridine is substituted by 0 to 3 (e.g., 0, 1, 2, or 3) R ¹² substituents, wherein each R ¹² is independently as defined herein, e.g, a halogen (e.g, F, Cl), a C6-10 aryl (e.g, phenyl), a heteroaryl, or a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl). In some aspects according to Formulae 7, 7a, and 7b, the pyridine ring is substituted by one, two, or three R ¹² substituents. In some aspects according to Formulae 7, 7a, and 7b, the pyridine ring is substituted by one R ¹² substituent, wherein the one R ¹² substituent is a fluorine or a phenyl, e.g, the pyridine ring is 3-fluoro-pyridine or 3 -phenyl -pyridine. In some aspects according to Formulae 7, 7a, and 7b, R ¹⁰ is selected from the group consisting of hexadecyl, eicosanyl and (2'-octyl)dodecyl; R ²⁰ is hydrogen or methyl; q is 4; p is 2; and the pyridine is 3-fluoro-pyridine or 3 -phenyl-pyridine.

[0140] In some aspects, an oxidized lipid of the invention is a compound having a structure according to Formula 8: or a stereoisomer, a stereoisomeric mixture, or a salt thereof. Suitable R ¹⁰ , R ²⁰ , and q are those as defined herein for Formula 5. In some aspects, the oxidized lipid has a zwittionic structure according to Formula 8. In some aspects, the oxidized lipid is an external salt (e.g, a pharmaceutically acceptable salt) of the compound having a structure according to Formula 8. In some aspects, the oxidized lipid according to Formula 8 has a structure according to Formula 8a or Formula 8b: F salt thereof.

[0141] In some aspects, the compound is a S-isomer having a structure according to

Formula 8a, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g, about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In some aspects, the compound is a R-isomer having a structure according to Formula 8b, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g. , about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In other aspects, the compound has an enantiomeric purity of from about 80% ee to about 100% ee, about 85% ee to about 100% ee, about 90% ee to about 100% ee, about 95% ee to about 100%, about 80% ee to about 99.5% ee, about 85% ee to about 99.5% ee, about 90% ee to about 99.5% ee, about 95% ee to about 99.5%, or any range thereof.

[0142] In some aspects according to Formula 8, R ¹⁰ is selected from the group consisting of hexadecyl, dodecyl, octadecyl, octyl, eicosanyl, cis-9-hexadecenyl, (2'-octyl)dodecyl, and (15'-carboxy)pentadecyl. In some aspects, R ¹⁰ is hexadecyl. In some aspects, R ¹⁰ is (2'-octyl)dodecyl. In some aspects, R ¹⁰ is eicosanyl.

[0143] In some aspects, R ²⁰ is a hydrogen or an alkyl. In some aspects, R ²⁰ is hydrogen.

In some aspects, R ²⁰ is an alkyl, e.g. , a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, iso-butyl, or tert-butyl). In some aspects, R ²⁰ is methyl.

[0144] In some aspects, q is an integer of 1-10, e.g, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some aspects, q is 4.

[0145] In some aspects, R ¹⁰ is selected from the group consisting of hexadecyl, eicosanyl, and (2'-octyl)dodecyl; R ²⁰ is hydrogen or a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl); and q is an integer of 2-6, e.g, 2, 3, 4, 5, or 6. In some aspects, R ¹⁰ is selected from the group consisting of hexadecyl, eicosanyl and (2'-octyl)dodecyl; R ²⁰ is hydrogen; and q is an integer of 2-6, e.g, 2, 3, 4, 5, or 6. In some aspects, R ¹⁰ is selected from the group consisting of hexadecyl, eicosanyl, and (2'-octyl)dodecyl; R ²⁰ is methyl; and q is an integer of 2-6, e.g ., 2, 3, 4, 5, or 6.

[0146] In some aspects, an oxidized lipid of the invention is a compound having a structure according to Formula 9,

P J

Formula 9 or a stereoisomer, a stereoisomeric mixture, or a salt thereof, wherein R ¹⁰ and R ²⁰ are as defined herein for Formula 5. In some aspects, the oxidized lipid has a zwittionic structure according to Formula 9. In some aspects, the oxidized lipid is an external salt (e.g, a pharmaceutically acceptable salt) of the compound having a structure according to Formula 9. In some aspects, the oxidized lipid is a compound according to Formula 9 has a structure according to Formula 9a or Formula 9b: or a salt thereof.

[0147] In some aspects, the compound is a S-isomer having a structure according to

Formula 9a, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g, about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In some aspects, the compound is a R-isomer having a structure according to Formula 9b, wherein the compound has an enantiomeric purity of about 80% ee or more, e.g, about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In other aspects, the compound has an enantiomeric purity of from about 80% ee to about 100% ee, about 85% ee to about 100% ee, about 90% ee to about 100% ee, about 95% ee to about 100%, about 80% ee to about 99.5% ee, about 85% ee to about 99.5% ee, about 90% ee to about 99.5% ee, about 95% ee to about 99.5%, or any range thereof [0148] In some aspects according to Formula 9, R ¹⁰ is selected from the group consisting of hexadecyl, dodecyl, octadecyl, octyl, eicosanyl, cis-9-hexadecenyl, (2'-octyl)dodecyl, and (15'-carboxy)pentadecyl. In some aspects, R ¹⁰ is hexadecyl. In some aspects, R ¹⁰ is (2'-octyl)dodecyl. In some aspects, R ¹⁰ is eicosanyl.

[0149] In some aspects, R ²⁰ is a hydrogen or an alkyl. In some aspects, R ²⁰ is hydrogen.

In some aspects, R ²⁰ is an alkyl, e.g ., a Ci-4 alkyl (e.g, methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, iso-butyl, or tert-butyl). In some aspects, R ²⁰ is methyl.

[0150] In some aspects, an oxidized lipid of the invention is a compound having a structure of: or a stereoisomer, a stereoisomeric mixture, or a salt thereof.

[0151] In some aspects, the invention provides a compound selected from the group consisting of (R)-l-hexadecyl-2-(4'-carboxy)butyl-sn-glycero-3 -phosphoric acid pyridiniumethyl ester (VB-701); (R)-l-eicosanyl-2-(4'-carboxy)butyl-sn-glycero-3- phosphoric acid pyridiniumethyl ester (VB-702); (R)-l-(2'-octyl)dodecyl-2-(4'- carboxy)butyl-sn-glycero-3-phosphoric acid pyridiniumethyl ester (VB-703); (R)-l- hexadecyl-2-(4'-carboxymethyl)butyl-sn-glycero-3 -phosphoric acid pyridiniumethyl ester (VB-704); and (R)-l-(2'-octyl)dodecyl-2-(4'-carboxymethyl)butyl-sn-glycero -3- phosphoric acid pyridiniumethyl ester (VB-705). The prefix "(R)-" refers to the configuration of the C-2 carbon of the glycerol backbone. In some aspects, the compound has an enantiomeric purity of about 80% ee or more, e.g., about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more.

[0152] In some aspects, an oxidized lipid of the invention is a compound having a structure of:

or a stereoisomer, a stereoisomeric mixture, or a salt thereof.

[0153] In some aspects, the invention provides a compound selected from the group consisting of (R)-l-(2'-octyl)dodecyl-2-(4'-carboxy)butyl-glycero-sn-3 -phosphoric acid 3- fluoro-pyridiniumethyl ester (VB-706) and (R)-l-(2'-octyl)dodecyl-2-(4'-carboxy)butyl- glycero-sn-3 -phosphoric acid 3-phenyl-pyridiniumethyl ester (VB-707). The prefix "(R)- " refers to the configuration of the C-2 carbon of the glycerol backbone. In some aspects, the compound has an enantiomeric purity of about 80% ee or more, e.g. , about 80% ee, about 85% ee, about 90% ee, about 91% ee, about 92% ee, about 93% ee, about 94% ee, about 95% ee, about 96% ee, about 97% ee, about 98% ee, about 99% ee, about 99.5% ee or more. In other aspects, the compound has an enantiomeric purity of from about 80% ee to about 100% ee, about 85% ee to about 100% ee, about 90% ee to about 100% ee, about 95% ee to about 100%, about 80% ee to about 99.5% ee, about 85% ee to about 99.5% ee, about 90% ee to about 99.5% ee, about 95% ee to about 99.5%, or any range thereof.

[0154] Oxidized lipids of the invention and methods for their synthesis have been described, for example, in International Publication Nos. WO 04/106486, WO 02/41827, WO 2011/083469, and WO 2016/084024.

Pharmaceutical Compositions

[0155] The methods of the present invention also encompass administration of a pharmaceutical composition comprising an oxidized lipid. [0156] Oxidized lipids of the invention can be administered to a subject in the form of a raw chemical or as part of a pharmaceutical composition, containing the oxidized lipid combined with a suitable pharmaceutically acceptable carrier. Such a carrier can be selected from pharmaceutically acceptable excipients, vehicles, and auxiliaries. The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable vehicle," or "pharmaceutically acceptable vehicle" encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0157] An oxidized lipid or pharmaceutical composition comprising an oxidized lipid can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intraci sternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration to a subject. Dosage forms depend on the route administration. Dosage forms include, but are not limited to, tablets, dragees, slow release lozenges, capsules, liquid suspensions, oral/nasal spray, transdermal patch, thin dissolvable film, ointments, sustained or controlled release implants, mouth rinses and mouth washes, gels, hair rinses, hair gels, and shampoos, and suppositories, as well as suitable solutions for administration by intravenous infusion, and suitable suspensions for administration subcutaneous injection, and suitable powders for reconstitution. Parenteral administration can be accomplished using a needle and syringe or using other technique known in the art.

[0158] Pharmaceutical compositions provided herein are manufactured by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. [0159] Suitable excipients are, in particular, fillers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxy methyl- starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries can be suitable flow-regulating agents and lubricants. Suitable auxiliaries include, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0160] Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are in one aspect dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

[0161] Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0162] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of oxidized lipid may be administered to a subject. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol -400. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers and other additives.

[0163] In one aspect, a pharmaceutical composition of the present invention can comprise an oxidized lipid ( e.g ., VB-201) and one or more optional therapeutic agents. Optional therapeutic agents include, but are not limited to, antiviral agents, antibiotic agents, antifungal agents, antiparasitic agents, antihelminthic drugs, immune modulating agents, anticoagulant agents, and anti-inflammatory agents, as described herein. In another aspect, the optional therapeutic agent is a drug considered a standard of care treatment for coronavirus infection (e.g., COVID-19). In another aspect, a drug considered a standard of care treatment for coronavirus infection (e.g., COVID-19) is an antiviral agent, an anticoagulant agent, a corticosteroid, or a combination thereof. In another aspect, a drug considered a standard of care treatment for coronavirus infection (e.g., COVID-19) is remdesivir, enoxaparin, dexamethasone, or a combination thereof. In another aspect, the methods of the present invention can be performed by administering an oxidized lipid (e.g., VB-201) in one pharmaceutical composition and one or more optional therapeutic agents in another pharmaceutical composition. In such an aspect, the compositions can be administered either sequentially or concomitantly.

Therapeutic Methods

[0164] An oxidized lipid, or composition thereof, can be administered to a subject in need thereof, e.g, a subject already suffering from inflammation or an infectious disease or symptom caused by a coronavirus infection, a subject suspected of having inflammation or an infectious disease or symptom caused by a coronavirus infection, or a subject at risk of acquiring inflammation or an infectious disease or symptom caused by coronavirus infection.

[0165] In one aspect, the disclosure provides a method for treating or preventing inflammation caused by a coronavirus infection comprising administering an oxidized lipid of the invention ( e.g ., VB-201), or a composition thereof. In another aspect, the disclosure provides an oxidized lipid (e.g., VB-201), or a composition thereof, for use in treating or preventing inflammation caused by a coronavirus infection. In another aspect, the disclosure provides the use of an oxidized lipid (e.g, VB-201) in the manufacture of a medicament for treating or prevention inflammation caused by a coronavirus infection.

[0166] In one aspect, the disclosure provides a method for treating or preventing an infectious disease or symptom caused by a coronavirus infection comprising administering an oxidized lipid of the invention (e.g., VB-201), or a composition thereof. In another aspect, the disclosure provides an oxidized lipid (e.g, VB-201), or a composition thereof, for use in treating or preventing an infectious disease or symptom caused by coronavirus infection. In another aspect, the disclosure provides the use of an oxidized lipid (e.g, VB-201) in the manufacture of a medicament for treating or preventing an infectious disease or symptom caused by a coronavirus infection.

[0167] In one aspect, the disclosure provides a method for treating or preventing hyper- inflammation caused by a coronavirus infection in a subject comprising administering an oxidized lipid of the invention (e.g., VB-201), or a composition thereof.

[0168] In one aspect, the disclosure provides a method for treating or preventing one or more symptoms of a subject infected with a coronavirus (e.g., COVID-19), comprising administration of an oxidized lipid of the invention (e.g., VB-201). In one aspect, the subject is asymptomatic or pre symptomatic and tests positive for a coronavirus infection by virologic testing using a molecular diagnostic (e.g., polymerase chain reaction test) or antigen test, but has no symptoms of a coronavirus infection. In one aspect, the subject has mild symptoms of a coronavirus infection, for example, fever, cough, sore throat, malaise, headache, muscle pain, or a combination thereof, without shortness of breath, dyspnea, abnormal chest imaging, or a combination thereof. In one aspect, the subject has moderate symptoms of a coronavirus infection, for example, evidence of lower respiratory disease by clinical assessment or imaging, and a saturation of oxygen (SpCh) >94% on room air at sea level. In one aspect, the subject has severe symptoms of a coronavirus infection, for example, respiratory frequency >30 breaths per minute, SpCh <94% on room air at sea level, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaCk/FiCh) <300 mmHg, lung infiltrates >50%, or a combination thereof.

[0169] In one aspect, the method results in reduced severity of one or more symptoms of a coronavirus infection, for example, improved rate of respiration (e.g., <30 breaths per minute), improved oxygen saturation (e.g., SpCk >94% on room air at sea level, and/or PaCh/FiCh >300 mmHg), lower blood pressure (diastolic and/or systolic), lower pulse rate (e.g., 51-90 beats per minute), improved consciousness, shorter time to recovery, reduced or eliminated clinical deterioration, reduced or eliminated c-reactive protein, reduced or eliminated lung infiltrates (<50%), or a combination thereof. In one aspect, administering an oxidized lipid of the invention (e.g., VB-201) results in the subject requiring no or reduced supplemental oxygen therapy.

[0170] In one aspect, the disclosure provides a method for treating or preventing symptoms caused by a viral infection in a subject comprising administering an oxidized lipid of the invention (e.g., VB-201), or a composition thereof. In one aspect, the disclosure provides a method for treating or preventing cytokine storm caused by a viral infection in a subject comprising administering an oxidized lipid of the invention (e.g., VB-201), or a composition thereof. In one aspect, the viral infection is a coronavirus infection, an influenza infection, or an H1N1 infection.

[0171] In another aspect, the coronavirus is a human coronavirus, or a mutated strain thereof, or an animal coronavirus, or a mutated strain thereof.

[0172] In another aspect, the human coronavirus is HCoV 229E, HCoV OC43, HCoV

NL63, HCoV HKU1, SARS CoV, MERS CoV, SARS CoV-1, or SARS CoV-2, or a mutated strain of HCoV 229E, HCoV OC43, HCoV NL63, HCoV HKU1, SARS CoV, MERS CoV, SARS CoV-1, or SARS CoV-2.

[0173] In another aspect, the coronavirus is a coronavirus described, for example, in the

GenBank database, a mutated variant thereof, or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity thereof. Exemplary coronavirus sequences also include, but are not limited to, any one of SEQ ID NOs: 1-4, a mutated variant thereof, or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity thereof.

[0174] Additional exemplary SARS-CoV-2 sequences include, but are not limited to,

GenBank Deposit Nos. LC522350, LC523807, LC523808, LC523809, LC528232, LC528233, LC529905, LR757995, LR757996, LR757997, LR757998, MC938385, MC938386, MC938387, MC938388, MC938389, MC938390, MN970003, MN970003, MN970004, MN975262, MN975263, MN975264, and MN975265, a mutated variant thereof, or a sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity thereof.

[0175] In one aspect, the oxidized lipid ( e.g ., VB-201) is administered to a subject having inflammation or an infectious disease or symptom caused by a coronavirus infection as a single agent.

[0176] In another aspect, the oxidized lipid (e.g., VB-201) is administered to a subject having inflammation or an infectious disease or symptom caused by a coronavirus infection in combination with one or more optional therapeutic agents. In another aspect, the oxidized lipid (e.g, VB-201) is administered to a subject having an infectious disease or symptom caused by a coronavirus infection in combination with one optional therapeutic agent. In another aspect, the oxidized lipid (e.g, VB-201) is administered to a subject having an infectious disease or symptom caused by a coronavirus infection in combination with two optional therapeutic agents. In another aspect, the oxidized lipid (e.g, VB-201) is administered to a subject having an infectious disease or symptom caused by a coronavirus infection in combination with three optional therapeutic agents. Optional therapeutic agents include, but are not limited to, antiviral agents, antibiotic agents, antifungal agents, antiparasitic agents, antihelminthic drugs, immune modulating agents, anticoagulant agents, and anti-inflammatory agents. In another aspect, the optional therapeutic agent is a drug considered a standard of care treatment for coronavirus infection (e.g., COVID-19). In another aspect, a drug considered a standard of care treatment for coronavirus infection (e.g., COVID-19) is an antiviral agent, an anticoagulant agent, a corticosteroid, or a combination thereof. In another aspect, a drug considered a standard of care treatment for coronavirus infection is remdesivir, enoxaparin, dexamethasone, or a combination thereof. [0177] Non-limiting exemplary antiviral agents include oseltamivir, ganciclovir, lopinavir/ritonavir (Kaletra®), and remdesivir. Antiviral agents also include reverse transcriptase inhibitors (RTIs). In one aspect, the RTI is a nucleoside reverse transcriptase inhibitors (NRTIs). Non-limiting exemplary NRTIs include abacavir (ZIAGENTM), abacavir/lamivudine (Epzicom), abacavir/lamivudine/zidovudine (TRIZIVIRTM), adefovir, alovudine, amdoxovir, apricitabine, ATRIPLA®, BARACLUDE®, BIKTARVY®, censavudine, COVIRACILTM, DAPD/DXG, D D4FC, dexelvucitabine, didanosine (VIDEXTM), didanosine extended-release (Videx EC), dOTC, EFdA, emtricitabine (EMTRIVATM), emtricitabine/tenofovir alafenamide (DESCOVY®), emtricitabine/tenofovir disoproxil fumarate (TRUVADA®), elvucitabine, fosalvudine, lamivudine/zidovudine (COMBIVIRTM), EVIPLERATM, GENVOYA®, HIVIDTM, KIVEXATM, lamivudine (EPIVIRTM), LODENOSINETM, ODEFSEY®, PREVEON®, racivir, stampidine, stavudine (ZERITTM), STRIBILD®, TENOFOVIRTM, tenofovir disoproxil fumarate (VIREADTM), TRIUMEQ®, Trizivir, VEMLIDY®, and zidovudine (RETROVIRTM). In another aspect, the RTI is a non nucleoside reverse transcriptase inhibitor (NNRTI). Non-limiting exemplary NNRTIs include delavirdine, efavirenz, etravirine, nevirapine, and rilvipirine. Antiviral agents also include protease inhibitors. Non limiting exemplary protease inhibitors include amprenavir, fosamprenavir, indinavir, nelfmavir, saquinavir, atazanavir, darunavir, and tipranavir. Antiviral agents also include, but are not limited to, antiviral antibodies ( e.g ., against any of the viruses described herein).

[0178] Non-limiting exemplary immune modulating agents include beta interferon, alpha interferon, phosphodiesterase 4 inhibitors, corticosteroids, convalescent serum/plasma, prostaglandin synthetase inhibitors, and monoclonal antibodies to inflammatory cytokines such as TNF, IL-1, IL-2, IL-6 and IL-10.

[0179] Non-limiting exemplary anti-inflammatory agents include an inhibitor of IL-6, nonsteroidal anti-inflammatory drugs (NSAIDs, e.g., ibuprofen, naproxen, meloxican, celecoxib, diclofenac sodium, prioxican, indomethacin, mefenamic acid, and etoricoxib (Arcoxia®)); asprin; cyclooxygenase (COX) inhibitors (e.g., COX-1 and COX-2 inhibitors); antileukotrienes (e.g., leukotriene-related enzyme inhibitors or leukotriene receptor antagonists); and immune selective anti-inflammatory derivatives (ImSAIDs). [0180] Nonsteroidal anti-inflammatory drugs can be counter-indicated in some subjects with COVID-19, as angiotensin-converting enzyme 2 (ACE2) is increased by NSAIDs and could aggravate COVID-19 symptoms. Thus, in one aspect, the anti-inflammatory agent is not an NS AID.

[0181] Non-limiting exemplary anticoagulant agents include coumarins, heparin, low molecular weight heparin, synthetic pentasaccharide inhibitors of factor Xa ( e.g ., fondaparinux, idraparinux, and idrabiotaparinux); oral anticoagulants (e.g., dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban, warfarin, and dicumarol); direct factor Xa inhibitors (e.g., rivaoxaban, apixaban, edoxaban, betrixaban, darexaban, letaxaban, and eribaxaban); direct thrombin inhibitors (e.g., hirudin, lepirudin and bivalirudin); antithrombin; batroxobin; hementin; and vitamin E.

[0182] In one aspect, the one or more optional therapeutic agents include remdesirivir, lopinavir/ritonavir, darunavir/cobicistat, sarilumab, chloroquine, umifenovir, baloxavir, favipiravir, and/or hydrochloroquine. In another aspect, the one or more optional therapeutic agents is a drug considered a standard of care treatment for coronavirus infection (e.g., COVID-19). In another aspect, a drug considered a standard of care treatment for coronavirus infection (e.g., COVID-19) is an antiviral agent, an anticoagulant agent, a corticosteroid, or a combination thereof. In another aspect, a drug considered a standard of care treatment for coronavirus infection is remdesivir, enoxaparin, dexamethasone, or a combination thereof.

[0183] Therapeutically effective amounts of an oxidized lipid formulated in accordance with standard pharmaceutical practices are administered to a subject in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment (diagnosis) that takes into consideration signs, symptoms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors. The exact formulation, route of administration, and dosage is determined by an individual physician in view of the diagnosed condition or disease. Dosage amount and interval can be adjusted individually to provide levels of oxidzed phospholipid that are sufficient to maintain therapeutic effects.

[0184] In one aspect, the methods of the present invention comprise administering an oxidized lipid at a therapeutically effective amount. The term "therapeutically effective amount," as used herein, refers to an amount of oxidized lipid sufficient to result in amelioration of one or more symptoms of a disorder or condition, or prevent appearance or advancement of a disorder or condition, or cause regression of or cure from the disorder or condition.

[0185] In some aspects, a therapeutically effective amount of oxidized lipid ( e.g ., VB-

201) is from about 5 mg to about 300 mg per day, for example, from about from about 20 mg to about 300 mg per day, from about 50 mg to about 300 mg per day, from about 80 mg to about 300 mg per day, from about 100 mg to about 300 mg per day, from about 160 mg to about 300 mg per day, from about 240 mg to about 300 mg per day, from about 5 mg to about 240 mg per day, from about 20 mg to about 240 mg per day, from about 50 mg to about 240 mg per day, from about 80 mg to about 240 mg per day, from about 100 mg to about 240 mg per day, from about 160 mg to about 240 mg per day, from about 5 mg to about 160 mg per day, from about 20 mg to about 160 mg per day, from about 50 mg to about 160 mg per day, from about 100 mg to about 160 mg per day, from about 5 mg to about 100 mg per day, from about 20 mg to about 100 mg per day, from about 50 mg to about 100 mg per day, from about 80 mg to about 100 mg per day, from about 5 mg to about 80 mg per day, from about 20 mg to about 80 mg per day, from about 50 mg to about 80 mg per day, from about 5 mg to about 50 mg per day, from about 20 mg to about 50 mg per day, or from about 5 to about 10 mg per day. In some aspects, the therapeutically effective amount of oxidized lipid (e.g., VB-201) is about 5 mg, about 10 mg, about 20 mg, about 40 mg, about 50 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 160 mg, about 200 mg, about 240 mg, or about 300 mg per day.

[0186] In some aspects, the daily therapeutically effective amount is administered to the subject in a single dose given once a day, or in multiple doses given twice a day, three times a day, four times a day, or five or more times a day. In some aspects, the oxidized lipid (e.g, VB-201) is administered at a dose of about 80 mg or about 100 mg, once, twice or three times a day. In some aspects, the oxidized lipid (e.g., VB-201) is administered at a dose of about 80 mg, twice a day (BID). In some aspects, the dose of about 80 mg is administered in two pharmaceutical compositions containing about 40 mg each. In some aspects, the composition is a capsule. In some aspects, the two doses are administered from about 10 hours to about 14 hours apart (e.g., about 12 hours). [0187] In some aspects, the oxidized lipid ( e.g ., VB-201) is administered with food. In some aspects, the oxidized lipid (e.g., VB-201) is administered from about two hours before food to about two hours after food.

[0188] In some aspects, the oxidized lipid (e.g., VB-201) is administered at a dose of from about 0.5 mg/kg to 5 mg/kg, for example, from about 0.5 mg/kg to about 4 mg/kg, from about 0.5 mg/kg to about 3 mg/kg, from about 0.5 mg/kg to about 2 mg/kg, from about 0.5 mg/kg to about 1 mg/kg, from about 1 mg/kg to about 5 mg/kg, from about 1 mg/kg to about 4 mg/kg, from about 1 mg/kg to about 3 mg/kg, from about 1 mg/kg to about 2 mg/kg, from about 2 mg/kg to about 5 mg/kg, from about 2 mg/kg to about 4 mg/kg, from about 2 mg/kg to about 3 mg/kg, from about 3 mg/kg to about 5 mg/kg, from about 3 mg/kg to about 4 mg/kg, or from about 4 mg/kg to about 5 mg/kg. In some aspects, the oxidized lipid (e.g, VB-201) is administered at a dose of about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, or about 5 mg/kg.

[0189] In some aspects, the oxidized lipid (e.g., VB-201) is administered from about 1 day to about 100 days, or longer, for example, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about

16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 30 days, about

40 days, about 50 days, about 60 days, about 70 days, about 80 days, or about 90 days.

[0190] In some aspects, the oxidized lipid (e.g., VB-201) is administered with food (e.g., from about two hours before food to about two hours after food) at a dose of about 80 mg, twice a day, in two pharmaceutical compositions containing about 40 mg each. In some aspects, the oxidized lipid (e.g., VB-201) is administered with food (e.g., from about two hours before food to about two hours after food) at a dose of about 80 mg, twice a day, in two pharmaceutical compositions containing about 40 mg each, for about 14 days. In some aspects, the oxidized lipid (e.g., VB-201) is administered with food (e.g., from about two hours before food to about two hours after food) at a dose of about 80 mg, twice a day, with from about 10 hours to about 14 hours between doses (e.g., about 12 hours) in two pharmaceutical compositions containing about 40 mg each, for about 14 days.

[0191] In some aspects, the methods of the present invention further comprise administration of chloroquine or hydroxychloroquine. In some aspects, the chloroquine or hydroxychloroquine is administered once a day, twice a day, three times a day, four times a day, or five or more times a day, at a dose of from about 50 mg to about 600 mg or more, for example, from about 100 mg to about 600 mg, from about 200 mg to about 600 mg, from about 240 mg to about 600 mg, from about 300 mg to about 600 mg, from about 400 mg to about 600 mg, from about 500 mg to about 600 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 240 mg to about 500 mg, from about 300 mg to about 500 mg, from about 400 mg to about 500 mg, from about 50 mg to about 400 mg, from about 100 mg to about 400 mg, from about 200 mg to about 400 mg, from about 240 mg to about 400 mg, from about 300 mg to about 400 mg, from about 50 mg to about 300 mg, from about 100 mg to about 300 mg, from about 200 mg to about 300 mg, from about 240 mg to about 300 mg, from about 50 mg to about 240 mg, from about 100 mg to about 240 mg, from about 200 mg to about 240 mg, from about 50 mg to about 200 mg, from about 100 mg to about 200 mg, or from about 50 mg to about 100 mg. In some aspects, the chloroquine or hydroxychloroquine is administered once a day, twice a day, three times a day, four times a day, or five or more times a day, at a dose of about 50 mg, about 100 mg, about 200 mg, about 240 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or more. In some aspects, the chloroquine or hydroxychloroquine is administered three times a day at a dose of about 200 mg. In some aspects, the chloroquine or hydroxychloroquine is administered three times a day at a dose of up to about 240 mg. In some aspects, the chloroquine or hydroxychloroquine is administered twice a day at a dose of about 600 mg ( e.g ., a loading dose). In some aspects, the chloroquine or hydroxychloroquine is administered twice on the first day at a dose of about 600 mg, followed by a dose of about 200 mg three times a day for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, or more.

[0192] In one aspect, the methods of the present invention comprise administration of an oxidized lipid (e.g., VB-201) to a subject in need thereof. The term "subject" as used herein refers to any human or animal that is in need of or might benefit from a method of the present invention. Foremost among such subjects are mammals, e.g, humans, although the methods and compositions provided herein are not intended to be so limited. Other subjects include veterinary animals, e.g, cows, sheep, pigs, horses, dogs, cats and the like. In one aspect, the subject is a human. In one aspect, the subject is an animal. In another aspect, the subject is a human infected with a human coronavirus. In another aspect, the subject is an animal infected with an animal coronavirus, e.g ., a feline coronavirus or a canine coronavirus.

[0193] In another aspect, the subject has been diagnosed with an infectious disease or symptom caused by a coronavirus infection (e.g, COVID-19), and optionally, the method is the prevention of lung disease.

[0194] In another aspect, the subject has a symptom of a coronavirus infection (e.g, of medium severity), and optionally, the method prevents need of a respirator for the subject.

[0195] In another aspect, the subject has a symptom of a coronavirus infection (e.g, of high severity), and optionally, the method shortens the number of days of hospitalization.

[0196] In one aspect, the method of treating or preventing inflammation caused by a coronavirus infection is directed to treating or preventing acute inflammation.

[0197] In one aspect, inflammation caused by a coronavirus infection is inflammation of or damage to the lung, heart, kidneys, central nervous system (CNS), stomach, and/or liver. In another aspect, the method of treating or preventing inflammation caused by a coronavirus infection reduces or eliminates inflammation in the lung, heart, kidneys,

CNS, stomach, and/or liver of the subject.

[0198] In one aspect, a reduction or elimination of inflammation associated with the methods of the present invention can be determined by (i) measurement of a biologic marker, such as a reduction in cytokine and/or C-reactive protein (CRP) levels and/or an increase in blood oxygen saturation, (ii) imaging, for example, with x-ray, CT scan, and/or PET-CT, and/or (iii) clinical signs, such as the need for ventilation, hospitalization (e.g., in an intensive care unit), and/or oxygen supplementation.

[0199] An oxidized lipid (e.g, VB-201) or pharmaceutical composition comprising an oxidized lipid (e.g, VB-201) can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracistemal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration to a subject. Dosage forms depend on the route administration. Dosage forms include, but are not limited to, tablets, dragees, slow release lozenges, capsules, liquid suspensions, oral/nasal spray, transdermal patch, thin dissolvable film, ointments, sustained or controlled release implants, mouth rinses and mouth washes, gels, hair rinses, hair gels, and shampoos, and suppositories, as well as suitable solutions for administration by intravenous infusion, and suitable suspensions for administration subcutaneous injection, and suitable powders for reconstitution. Parenteral administration can be accomplished using a needle and syringe or using other technique known in the art.

[0200] In one aspect, administration of an oxidized lipid ( e.g ., VB-201) results in the inhibition of activity of TLR2, TLR4 and/or CD14 in a cell of the subject. In another aspect, the activity of TLR2 and TLR4 is inhibited; activity of TLR4 and CD14 is inhibited; activity of TLR2 and CD 14 is inhibited; or activity of TLR2, TLR4 and CD 14 is inhibited.

[0201] In another aspect, administration of an oxidized lipid (e.g., VB-201) results in the inhibition of monocyte migration.

[0202] In another aspect, administration of an oxidized lipid (e.g., VB-201) results in the inhibition of monocyte migration and inhibition of activity of TLR2, TLR4 and/or CD14 in a cell of the subject. In another aspect, monocyte migration and activity of TLR2 and TLR4 are inhibited; monocyte migration and activity of TLR4 and CD 14 are inhibited; monocyte migration and activity of TLR2 and CD 14 are inhibited; or monocyte migration and activity of TLR2, TLR4 and CD 14 are inhibited.

[0203] In another aspect, administration of an oxidized lipid (e.g., VB-201) results in the inhibition of activity of sperm domain-containing protein 2 (MOSPD2). In another aspect, administration of an oxidized lipid (e.g., VB-201) results in the inhibition of activity of MOSPD2 and one or more of the following: inhibition of monocyte migration, inhibition of activity of TLR2, inhibition of activity of TLR4, and inhibition of activity of CD14.

Kits

[0204] In another aspect, the present disclosure provides kits comprising an oxidized lipid (e.g, VB-201) or a composition comprising an oxidized lipid (e.g, VB-201) packaged in a manner that facilitates their use to practice methods of the present disclosure. [0205] In one aspect, the kit includes an oxidized lipid ( e.g ., VB-201), or a pharmaceutical composition thereof, packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or pharmaceutical composition to practice the method of the disclosure. In one aspect, the compound or composition is packaged in a unit dosage form. The kit may include a single dose or multiple doses of an oxidized lipid (e.g., VB-201), or a pharmaceutical composition thereof.

EXAMPLES

[0206] Reference is now made to the following Examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

EXAMPLE 1

[0207] A Phase 2 randomized controlled study is performed to evaluate the efficacy and safety of VB-201 in patients with moderate COVID-19. The following protocol is used:

Study Rationale

[0208] Coronavirus disease 2019 (COVID-19) is caused by the single stranded RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and can be accompanied by a marked inflammatory response, which is believed to be detrimental to the patient and associated with multi-organ dysfunction, respiratory failure and death.

Hypothesis

[0209] Combination treatment with oral VB-201 and hydroxychloroquine will prevent clinical deterioration, shorten the hospitalization and reduce morbidity and mortality in patients with moderate COVID-19 compared to standard of care.

Objectives and Endpoints

[0210] Combination treatment with oral VB-201 and hydroxychloroquine will prevent clinical deterioration, and reduce morbidity and mortality in patients with moderate COVID-19 compared to standard of care treatment with hydroxychloroquine alone, as summarized in Table 1. Table 1 : Summary of Study Objectives and Endpoints

Overall Study Design

[0211] This is a randomized phase 2 controlled study of VB-201 and hydroxychloroquine vs. placebo and hydroxychloroquine to evaluate efficacy and safety, in patients with moderate COVID-19. VB-201 or matching placebo will be administered orally at a dose of 80 mg BID for 14 days together with Hydroxychloroquine given with a loading dose of 600 mg x 2 followed by 200 mg x 3 every day for 10 days.

[0212] The study population will consist of hospitalized patients >18 years old with

COVID-19 of moderate severity defined as radiologic evidence of pneumonia and a need for supplemental oxygen.

[0213] The enrollment will be stratified by the use of concomitant therapies: an antiviral

(e.g., remdesivir), anti-inflammatory biologies targeting, e.g., IL-6 or IL-1, or both antiviral and anti-inflammatory therapies or neither. As an alternative, concomitant therapies will be excluded. Nonsteroidal anti-inflammatory drugs (NSAIDs) will not constitute anti-inflammatory agents for the purposes of stratification.

Number of Patients

[0214] Approximately 200 patients will be randomized in 1 : 1 ratio to receive either VB-

201 and hydroxychloroquine, or placebo and hydroxychloroquine.

Eligibility

[0215] Inclusion criteria is as follows: • Age >18 years

• Confirmed SARS-2-CoV-2 infection by polymerase chain reaction (PCR)

Hospitalized

• Informed consent

• Has symptoms of moderate COVID-19 as demonstrated by radiologic evidence of pneumonia and requires oxygen supplementation

• Use of highly effective methods of contraception throughout the study and for 1 week following the last dose of study treatment.

• Negative pregnancy test for females with childbearing potential

[0216] Exclusion criteria is as follows:

1. Evidence of sever e/criti cal COVID-19 based on any of the following a. Respiratory rate >24 breaths/minute b. Pulse Oxygen Saturation (Sp02) <93% without oxygen supplementation, c. Admission to ICU d. Mechanical ventilation (invasive or non-invasive) e. ECMO or hemofiltration required f. Shock

2. In the opinion of the investigator, unlikely to survive for at least 48 hours from screening or anticipate mechanical ventilation within 48 hours 3. Unable to take oral medication

4. Hypersensitivity to any of the study drugs

5. Participation in another interventional clinical trial during the course of the study

Study Treatment. Dose and Mode of Administration

[0217] Treatment arm: Oral VB-201 80 mg BID given daily for 14 days with hydroxychloroquine given with a loading dose of 600 mg x 2 followed by 200 mg x 3 every day for 10 days.

[0218] Control arm: placebo BID for 14 days with hydroxychloroquine given with a loading dose of 600 mg x 2 followed by 200 mg x 3 every day for 10 days.

EXAMPLE 2

[0219] A Phase 2 randomized controlled study is performed to evaluate the efficacy and safety of VB-201 in patients with COVID-19 infection.

[0220] In brief, the primary objective is to examine the safety and tolerability of treatment with VB-201 in male and female patients, 18-80 years of age, with severe COVID-19 infection. More specifically, the exploratory efficacy objectives are to examine the effect of treatment with VB-201 on (1) change in the subject's clinical status using the WHO clinical progression scale (Table 2), (2) national early warning score 2 (NEWS2 score), (3) time to recovery, (4) proportion of subjects who have clinical deterioration, and (5) C-reactive protein (CRP) levels.

Table 2: WHO clinical progression scale

[0221] The National Early Warning Score (NEWS) was launched by the Royal College of Physicians (RCP) to improve the identification, monitoring and management of unwell patients in hospital. It is based on a logistic regression model designed to predict in- hospital patient mortality within 24 hours of a set of vital sign observations. NEWS2 is based on a simple aggregate scoring of six simple physiological parameters: respiration rate, oxygen saturation (with or without oxygen supplementation), systolic blood pressure, pulse rate, and level of consciousness or new confusion.

Study Design

[0222] The study is designed to test safety, efficacy, and tolerability of an oral preparation of VB-201 in patients with severe COVID-19 infection.

[0223] Subjects are screened for eligibility (Day 1), and up to 1 day later randomized on a 1 : 1 ratio to one of two treatment groups: VB-201 160 mg (80 mg BID) with standard of care treatment, or standard of care treatment alone. Each dose is two capsules (40 mg per capsule, 80 mg total dose), administered orally twice daily at breakfast time and at dinner time (160 mg total daily dose). Morning (AM) and Evening (PM) doses of VB-201 are taken with food 12 ± 2 hours apart, for a total of 14 days. [0224] Subjects will be assessed during visits occurring on Day 3, 8, 15 and 21 of the study. Each subject will have a final safety visit, 4 weeks after stopping treatment with study drug.

[0225] The following study assessments are performed at all visits (medical facility site visits, home visits and telephone visits): WHO Clinical Progression Scale, Adverse Events and Concomitant medications.

[0226] The following study assessments are performed only at site visits: Inclusion/

Exclusion Criteria Assessment, Medical History, Demographic information; Physical Examination, Vital Signs (performed also on home visits), NEWS Scoring (performed also on home visits), Blood sample (hematology, biochemistry, pregnancy, CRP); (performed also on home visits), ECG (12-lead) (performed also on home visits) and Chest X-Ray.

[0227] This is an adaptive trial. Enrollment will occur in the three stages. In Stage 1, after the enrollment of the 30 subjects, safety and efficacy data is evaluated by the principal investigator (PI), summarized in a report, and submitted to the Institute Review Board (IRB). IRB will grant approval to continue enrolment. In Stage 2, following IRB approval, enrollment of 70 additional subjects will continue. After the enrollment of a total of 100 subjects, safety and efficacy data is evaluated by the PI, summarized in a report, and submitted to IRB. IRB will grant approval to continue enrollment. In Stage 3, following IRB approval, enrollment of up to 100 additional subjects may continue to a maximum of 200 patients.

Dosage Regimen and Treatment Groups

[0228] Patients are randomly assigned (1 : 1) to one of the two treatment arms. The two treatment arms are (1) daily oral administration of 160 mg VB-201 (80 mg BID) with standard of care treatment, and (2) standard of care treatment. Morning (AM) and evening (PM) doses of VB-201 are taken with food 12 ± 2 hours apart. Treatment will continue for 14 days.

Duration of Participation

[0229] Patients will remain on therapy for up to 14 days and participate in the study for up to 7 weeks. Specifically, patients will participate in 1 day of screening, followed by 14 days of treatment [VB-201 80 mg BID with standard of care treatment, or standard of care treatment], and a final follow-up visit 4 weeks after the last dose of study medication.

Eligibility Criteria

[0230] Subjects who meet all of the following criteria will be considered for enrollment into this study.

Inclusion Criteria

1. Fully understand all elements of and have signed and dated the written IRB or Independent Ethics Committee (IEC) approved informed consent before initiation of protocol-specified procedures.

2. Male or female subjects >18 to <80 years of age with COVID-19.

3. SARS-2-CoV-2 infection confirmed by PCR test in the last 8 days.

4. Hospitalized

5. Severe COVID-19 as demonstrated by one of the following:

• Respiratory frequency >30 breaths per minute

• Oxygen saturation (Sp02) <94% on room air at sea level

• Ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (Pa02/Fi02) <300 mmHg

• Lung infiltrates >50%

6. For a female subject, either: subject is non-childbearing, defined as menopausal with amenorrhea >1 years, hysterectomy, or bilateral oopherectomy, or agrees to continue to use highly effective methods of birth control defined as those alone or in combination that result in a low failure rate (<1%) when used consistently and correctly throughout the study and for at least one month following treatment termination and have a negative pregnancy test at screening and before the first dose of study drug;

[0231] Males must use at least one method of contraception ( e.g ., condom) throughout the study and for 90 days following the last dose of study drug; 7. In the opinion of the PI, the subject will be compliant and have a high probability of completing the study and all required procedures.

Exclusion Criteria

Subjects who meet any of the following criteria are excluded from participation in this study:

1. Evidence of critical COVID-19 based on any of the following: admission to an intensive care unit (ICU), assisted ventilation (invasive or non-invasive), ECMO or hemofiltration required, acute respiratory distress syndrome (ARDS), shock, or acute cardiac failure.

2. Dementia.

3. Bacterial co-infection.

4. Co-infection with other common viral pneumonias (e.g., influenza)

5. Participation in another interventional clinical trial or intention to participate in another interventional study during the course of this study.

6. In the opinion of the PI, unlikely to survive for at least 48 hours from screening or anticipate mechanical ventilation within 48 hours.

7. Unable to take oral medication.

8. History of gastrointestinal illness that may cause nausea and vomiting.

9. Subjects with any laboratory test at screening that common medical practice would deem as significantly abnormal (for example, alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phosphatase at >5.0-times the upper limit of normal (ULN) or creatinine clearance at <30 mL/min).

10. The subject has a known allergy or sensitivity to the study treatment(s) or to any of the excipients contained in the study drug formulation;

11. Female subject with a positive pregnancy test or nursing, or planning a pregnancy during the course of the study;

12. Unwilling or unable to comply with study requirements.

Concomitant Medications

[0232] Concomitant administration of other investigational medications in any other clinical trial is prohibited. Medications for COVID-19 that are given outside the scope clinical trials are administered according to the judgement of the PI (e.g., antiviral medications, enoxaparin, dexamethasone, azithromycin, and/or plasma). Primary Endpoint

[0233] The primary endpoint of the study is to assess the safety and tolerability of VB- 201. Safety is assessed based on all subjects in the study who have received at least one dose of study drug (Safety Population) and includes adverse events (AE), treatment discontinuations due to AE, vital signs, safety laboratory biochemistry, hematology, and electrocardiogram (ECG).

Exploratory Efficacy Endpoints

[0234] The following exploratory efficacy endpoints are used in the study.

• Change in clinical status from baseline to day 21 as assessed by the mean change in the WHO clinical progression scale.

• Mean change in NEWS2 score from baseline until day 21.

• Time to recovery. Recovery is defined as either discharge from the hospital or medically ready for discharge, but remain in the hospital due to quarantine/public health measures or due to no other living arrangements yet available.

• Time to meeting NEWS 2 Score <=2.

• Proportion of subjects who had clinical deterioration defined as either admission to ICU, need for mechanical ventilation or ECMO, death or high CRP.

Study Conduct

[0235] Hospitalized patients with severe COVID-19 who meet the study eligibility criteria will be identified and considered for screening. Screening is performed after signing an informed consent. Following screening, eligible subjects are randomized to one of the treatment arms using a preestablished randomization list. Subjects are treated for 14 days. Subjects who were discharged before day 14 will continue to take study drug at home until day 14 and will be asked to document medication administration at home on a medication diary.

[0236] Study visits are performed at Screening/Baseline, Day 3, 8, 15, 21, and a final safety follow up (FU) visit 4 weeks after the last dose of study drug. Day 8 and Day 15 visits are performed at the site for hospitalized patients and as a telephone visit for subjects who were discharged. Subjects, including those who discontinued treatment prematurely will perform Day 21 visit at the site. However, for discharged patients who do not meet the COVID-19 recovery criteria for non-infectiveness to by day 21+3, the visit will be performed at the subject's home by a delegated study member. The final follow-up visit is performed as a phone visit 4 weeks after the last dose of study medication.

[0237] Data collection will be via electronic data capture (EDC) system CRFs.

Statistical Methods

[0238] The exploratory efficacy analyses are completed in the Intent-To-Treat (ITT) population. This population will include all subjects who have signed a consent form and undergone randomization, according to the treatment group to which they were allocated. Efficacy analyses will also be completed in a Per-Protocol population; these will be exploratory. Categorical data is presented as counts and percentages. Continuous data is presented as summary statistics. All statistical comparisons are two-sided at the 5% level of significance.

[0239] All publications, patents and patent applications mentioned in this application are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.