ANTIVIRAL RUTHENATE(III) THERAPEUTICS

FIELD

[0001] The invention is in the field of therapeutic compounds, particularly the use of sodium trans-[tetrachloridobis(1H-indazole)ruthenate(lll)] for treating viral diseases.

BACKGROUND

[0002] Sodium trans-[tetrachloridobis(1 H-indazole)ruthenate(lll)] is a coordinated complex of ruthenium having anticancer activity (also known as BOLD-100, KP1339, NKP-1339, IT-139, and Na[Ru ^m CU(Hind)2]). Methods of making alkali metal salts of trans-[tetrachlorobis(1 H-indazole)ruthenate(lll)] are for example described in WO201 8204930, such as compounds having Formula I:

I wherein M is an alkali metal cation, including the sodium salt:

[0003] Glucose regulated protein 78 (GRP78, also referred to as BiP or HSPA5, a member of the Hsp70 family of heat shock proteins), is a master-regulator of the endoplasmic reticulum (ER) stress response. In unstressed cells, GRP78 is typically found at low levels and located in the lumen of the ER, where it facilitates folding and assembly of proteins, translocation across the ER membrane, and the tagging of misfolded proteins for degradation. In unstressed cells, ER stress proteins are understood to be maintained in an inactive form by the binding of GRP78. Under conditions of stress, higher levels of mis-folded proteins are generated that in turn bind to GRP78, releasing ER stress proteins from GRP78-mediated inactivity, resulting in the initiation of a cascade of activities involved in an unfolded protein response. In stressed cells, GRP78 is significantly up-regulated and also found outside the ER in the cell cytoplasm, the nucleus, in the mitochondria, on the cell surface and secreted. There is a complex interaction of the ER stress response and viral infection (Jheng, Jia-Rong et al. Frontiers in microbiology vol. 5388. 5 Aug. 2014). BOLD-100 has been described as selectively suppressing GRP78 up-regulation in cancer cells, supressing GRP78 transcription (WO2017151762).

[0004] The emerging global coronavirus-infected disease 2019 (COVID-19) is caused by a novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2; NCBI Reference Sequence: NC_045512.2), classified by the World Health Organisation (WHO) as a b coronavirus (CoV) of group 2B. The coronaviruses are members of a family of enveloped viruses that replicate in the cytoplasm of animal host cells, distinguished by the presence of a single-stranded plus sense RNA genome, approximately 30 kb in length, that has a 5' cap structure and 3'polyA tract (essentially a very large mRNA). Upon infection of an appropriate host cell, the 5'-most open reading frame (ORF) of the viral genome is translated into a large polyprotein that is cleaved by viral-encoded proteases to release several nonstructural proteins including an RNA- dependent RNA polymerase (Pol) and an ATPase helicase (Hel). These proteins in turn are responsible for replicating the viral genome as well as generating nested transcripts that are used in the synthesis of the viral proteins. The coronaviral membrane proteins, including the major proteins S (Spike) and M (Membrane), are inserted into the endoplasmic reticulum Golgi intermediate compartment (ERGIC) while full length replicated RNA (+ strands) assemble with the N (nucleocapsid) protein. This RNA- protein complex then associates with the M protein embedded in the membranes of the ER, and virus particles form as the nucleocapsid complex buds into the ER. The virus then migrates through the Golgi complex and eventually exits the cell, presumptively by exocytosis.

[0005] The site of SARS-CoV-2 attachment to the host cell is understood to reside within the spike (S) glycoprotein (NCBI Ref Seq YP_009724390.1). It is understood that during viral infection, trimeric S protein is cleaved into S1 and S2 subunits, S1 subunits are released containing a receptor binding domain (RBD), which is understood to bind to the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2), while S2 is responsible for membrane fusion in a process that requires S2 cleavage by host proteases (Renhong Yan et al. , Science 27 March 2020, Vol. 367, Issue 6485, 1444- 1448).

[0006] An antiviral activity has been suggested for select substituted phenyl- heteroaryl-aryl compounds characterized as acting to inhibit an enzymatic activity of GRP78 (WO2018026812). GRP78 has been described as a host factor in involved in a variety of viral infections (Ibrahim, Ibrahim M et al. Life sciences vol. 226 (2019): 156- 163.; Zhao, Dongmin et al. Frontiers in microbiology vol. 9694. 9 Apr. 2018).

SUMMARY

[0007] Methods are provided for therapeutically or prophylactically treating a viral disease caused by a virus infection in a subject in need thereof, comprising administering to the subject an effective amount of sodium trans-[tetrachloridobis(1H- indazole)ruthenate(lll)]. The subject may be a human patient, for example a geriatric or immunocompromised patient. The virus may be a coronavirus or a b coronavarius of group 2B, for example having a genomic nucleotide sequence that is at least 95%, 99%, 99.5% or 99.9% identical to SARS-CoV-2 genomic sequence (NCBI Reference Sequence: NC_045512.2). The coronavirus may be a virus that expresses a spike (S) glycoprotein that binds to glucose regulated protein 78 (GRP78), or a coronavirus comprises a spike glycoprotein sequence that is at least 95%, 99%, 99.5% or 99.9% identical to SARS-CoV-2 spike glycoprotein sequence (NCBI Reference Sequence: YP_009724390.1). The SARS-CoV-2 coronavirus may be a Variant of Interest or a Variant of Concern, for example having specific sequence variations from the reference SARS-CoV-2 genomic sequence (NCBI Reference Sequence: NC_045512.2). The coronavirus may be Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the coronavirus disease may be coronavirus-infected disease 2019 (COVID-19). Corresponding uses of sodium trans-[tetrachloridobis(1 H-indazole)ruthenate(lll)] are similarly provided.

[0008] Alternatively, the virus may be one or more of: Adenovirus, Herpes simplex, type 1, Herpes simplex, type 2, Varicella-zoster virus, Epstein-barr virus, Human cytomegalovirus, Human herpesvirus, type 8, Human papillomavirus, BK virus, JC virus, Smallpox, Hepatitis B virus, Human bocavirus, Parvovirus B19, Human astrovirus, Norwalk virus, coxsackievirus, hepatitis A virus, poliovirus, rhinovirus, Severe acute respiratory syndrome virus, Hepatitis C virus, yellow fever virus, Hepatitis E virus, and Human immunodeficiency virus (HIV), Ebola virus, Marburg virus, Zika virus, Dengue virus, Japanese encephalitis virus, St. Louis encephalitis, West Nile virus, tick-borne encephalitis virus, Influenza A, Influenza B, Influenza C, avian influenza, swine influenza, measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus, coxsackie virus, rabies virus and vesicular stomatitis virus and rubella virus.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 is a line graph, illustrating antiviral efficacy of BOLD-100 against SARS-CoV-2.

[0010] Figure 2 includes four line graphs, illustrating antiviral efficacy of BOLD- 100 against SARS-CoV-2, compared to Remdesivir, in a post-infection treatment model. [0011] Figure 3 includes four line graphs, illustrating antiviral efficacy of BOLD- 100 against SARS-CoV-2, compared to Remdesivir, in a pre-infection treatment model. [0012] Figure 4A and 4B include, respectively, a bar graph and a line graph illustrating nucleocapsid protein and RNA levels in a 293T-ACE2 human cell line infected with SARS-CoV-2 (strain 2019-nCoV/USA-WA-1/2020), illustrating antiviral efficacy of BOLD-100 against SARS-CoV-2.

[0013] Figure 5 is a line graph showing dose-dependent inhibition of viral release by BOLD-100 in human kidney 293T-ACE2 cells infected with SARS-CoV-2 (strain 2019-nCoV/USA-WA-1/2020), illustrating antiviral efficacy of BOLD-100 against SARS- CoV-2

[0014] Figure 6 includes 3 micrographs, showing cellular survival at 200uM BOLD-100 in human kidney 293T-ACE2 cells infected with a SARS-CoV-2 variant of concern (MOI= 0.001) (SARS-CoV-2 Isolate hCoV-19/USA/CA_CDC_5574/2020- B.1.1.7 variant: isolated from a nasopharyngeal swab collected on December 29, 2020 in San Diego County, California, USA), illustrating antiviral efficacy of BOLD-100 against a SARS-CoV-2 variant of concern.

[0015] Figure 7 is a line graph illustrating antiviral efficacy of BOLD-100 against SARS-CoV-2 in A549-ACE2 lung cells.

DETAILED DESCRIPTION

[0016] One aspect of the current innovations provides a method for preparing a sterile, lyophilized drug product containing sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], suitable for administration to a patient, for use in treating a coronaviral disease caused by a coronavirus infection. The formulation is comprised of sodium frans-[tetrachlorobis(1H-indazole)ruthenate (III)], a pH buffer, and a cryoprotective agent. The general method for providing said formulation comprises the steps of preparing aqueous buffer solution, preparing aqueous cryoprotectant solution, dissolution of sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] in the buffer solution, addition of the cryoprotectant solution, sterile filtration (e.g. aseptic filtration), filling of vials under sterile conditions, and lyophilization under sterile conditions.

Suitable buffers include, but are not limited to: citrate, TRIS, acetate, EDTA, HEPES, tricine, and imidazole. The use of a phosphate buffer is possible but is not preferred.

An aspect of the present innovations is the use of a citric acid/sodium citrate buffer. Suitable cryoprotective agents include, but are not limited to: sugars, monosaccarides, disaccharides, polyalcohols, mannitol, sorbitol, sucrose, trehalose, dextran, and dextrose. An aspect of the present innovations is the use of mannitol as the cyroprotecive agent.

[0017] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], a suitable buffer, and mannitol, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease. In some embodiments, a suitable buffer comprises a citrate buffer. For instance, in some embodiments, a citrate buffer comprises sodium citrate and citric acid.

[0018] Compositions are provided comprising sodium trans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, and mannitol, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease.

[0019] Compositions are provided comprising sodium trans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, and mer,trans- [Ru ^IN Cl3(Hind)2(H20)], for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease.

[0020] Compositions are provided comprising sodium trans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease.

[0021] Compositions are provided comprising sodium trans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, and mannitol, wherein the sodium trans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is amorphous, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease.

[0022] Compositions are provided comprising sodium trans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, and mer,trans- [Ru ^IN Cl3(Hind)2(H20)], wherein the sodium trans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is amorphous, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease.

[0023] Compositions are provided comprising sodium trans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, wherein the sodium trans-[tetrachlorobis(1 H- indazole)ruthenate (III)] is amorphous, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease. [0024] Compositions are provided comprising sodium trans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein:

/7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is between about 0.01 and about 0.4 weight percent of the composition, and cesium is between about 0.00001 and about 0.01 weight percent of the composition.

[0025] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein:

/7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is between about 0.01 and about 0.4 weight percent of the composition, and cesium is between about 0.00001 and about 0.01 weight percent of the composition.

[0026] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein:

/7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is between about 0.01 and about 0.2 weight percent of the composition, and cesium is between about 0.00001 and about 0.01 weight percent of the composition.

[0027] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], /7?er,frans-[Ru ^m Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein:

/7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is between about 0.01 and about 0.40 weight percent of the composition, and cesium is between about 0.00001 and about 0.01 weight percent of the composition.

[0028] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], /7?er,frans-[Ru ^m Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: the composition is a lyophilized powder,

/7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is between about 0.01 and about 0.40 weight percent of the composition, and cesium is between about 0.00001 and about 0.01 weight percent of the composition.

[0029] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: the composition is a lyophilized powder,

/7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is between about 0.01 and about 0.3 weight percent of the composition, and cesium is between about 0.00001 and about 0.1 weight percent of the composition.

[0030] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein:

/7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is between about 0.01 and about 0.3 weight percent of the composition, and cesium is between about 0.00001 and about 0.1 weight percent of the composition.

[0031] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: the composition is a lyophilized powder, sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 11.5 to about 14.0 weight percent of the compositon, citric acid is about 43.9 to about 53.7 weight percent of the composition, sodium citrate is about 25.7 to about 23.1 weight percent of the composition, mannitol is about 11.5 to about 14.0 weight percent of the composition, /7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is about 0.01 and about 0.3 weight percent of the composition, and cesium is between about 0.00001 and about 0.1 weight percent of the composition.

[0032] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: the composition is a lyophilized powder, sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 10.2 to about 15.3 weight percent of the composition, citric acid is about 39.0 to about 58.5 weight percent of the composition, sodium citrate is about 20.5 to about 30.8 weight percent of the compositon, mannitol is about 10.2 to about 15.3 weight percent of the composition, mer,frans-[ u ^m Cl3(Hind) ₂ (H ₂ 0)] is about 0.01 and about 0.3 weight percent of the composition, and cesium is between about 0.00001 and about 0.1 weight percent of the composition.

[0033] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], sodium citrate, citric acid, mannitol, mer,trans- [Ru ^IN Cl3(Hind)2(H20)], and a cesium salt, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: the composition is a lyophilized powder, sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 10.2 to about 15.3 weight percent of the composition,

/7?er,frans-[Ru ^m Cl3(Hind)2(H20)] is about 0.01 and about 0.3 weight percent composition, and cesium is between about 0.00001 and about 0.1 weight percent of the composition.

[0034] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, and sodium citrate, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 49.86 weight percent of the composition, mannitol is about 49.86 weight percent of the composition, citric acid is about 0.187 weight percent of the composition, and sodium citrate is about 0.093 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder.

[0035] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, and sodium citrate, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 40 to about 60 weight percent of the composition, mannitol is about 40 to about 60 weight percent of the composition, citric acid is about 0.01 to about 0.5 weight percent of the composition, and sodium citrate is about 0.001 to about 0.25 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder. [0036] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, and sodium citrate, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 30 to about 70 weight percent of the composition, mannitol is about 30 to about 70 weight percent of the composition, citric acid is about 0.001 to about 1 weight percent of the composition, and sodium citrate is about 0.0001 to about 1 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder. [0037] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, and Ru ^IN Cl3(Hind)2(H20), for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 49.86 weight percent of the composition, mannitol is about 49.86 weight percent of the composition, citric acid is about 0.187 weight percent of the composition, sodium citrate is about 0.093 weight percentage of the composition, and Ru ^m Cl3(Hind)2(H20) is not more than 0.5 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder. [0038] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, and Ru ^IN Cl3(Hind)2(H20), for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 40 to about 60 weight percent of the composition, mannitol is about 40 to about 60 weight percent of the composition, citric acid is about 0.01 to about 0.5 weight percent of the composition, sodium citrate is about 0.001 to about 0.25 weight percentage of the composition, and Ru ^m Cl3(Hind) ₂ (H ₂ 0) is about 0 to about 0.5 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder. [0039] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, Ru ^m Cl3(Hind)2(H20), and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 30 to about 70 weight percent of the composition, mannitol is about 30 to about 70 weight percent of the composition, citric acid is about 0.001 to about 1 weight percent of the composition, sodium citrate is about 0.0001 to about 1 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than 0.5 weight percentage of the composition, and cesium is not more than 0.25 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder.

[0040] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 49.61 weight percent of the composition, mannitol is about 49.86 weight percent of the composition, citric acid is about 0.187 weight percent of the composition, sodium citrate is about 0.093 weight percentage of the composition and cesium is about 0.25 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder.

[0041] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 40 to about 60 weight percent of the composition, mannitol is about 40 to about 60 weight percent of the composition, citric acid is about 0.01 to about 0.5 weight percent of the composition, sodium citrate is about 0.001 to about 0.25 weight percentage of the composition, and cesium is about 0.1 to about 0.5 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder. [0042] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 30 to about 70 weight percent of the composition, mannitol is about 30 to about 70 weight percent of the composition, citric acid is about 0.001 to about 1 weight percent of the composition, sodium citrate is about 0.0001 to about 1 weight percentage of the composition, and cesium is about 0.01 to about 1 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder.

[0043] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, Ru ^m Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), Ru ^m Cl3(Hind)(HN=C(Me)ind), and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] about 46.61 weight percent of the composition, mannitol is about 49.86 weight percent of the composition, citric acid is about 0.187 weight percent of the composition, sodium citrate is about 0.093 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than 0.5 weight percentage of the composition, Ru ^IN Cl3(Hind)2(CH3CN) is not more than 1.25 weight percentage of the composition,

Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than 1 .0 weight percentage of the composition, and cesium is not more than 0.25 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder. [0044] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, Ru ^m Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), Ru ^m Cl3(Hind)(HN=C(Me)ind), and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] about between 46.61 weight percent of the composition, mannitol is about 49.86 weight percent of the composition, citric acid is about 0.187 weight percent of the composition, sodium citrate is about 0.093 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than 0.5 weight percentage of the composition, Ru ^m Cl3(Hind)2(CH3CN) is not more than 1.25 weight percentage of the composition,

Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than 1 .0 weight percentage of the composition, and cesium is not more than 0.25 weight percentage of the composition. In some such embodiments, the composition is a lyophilized powder.

[0045] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, Ru ^m Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), Ru ^m Cl3(Hind)(HN=C(Me)ind), and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 40 to about 60 weight percent of the composition, mannitol is about 40 to about 60 weight percent of the composition, citric acid is about 0.01 to about 0.5 weight percent of the composition, sodium citrate is about 0.001 to about 0.25 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than about 0.5 weight percentage of the composition,

Ru ^m Cl3(Hind)2(CH3CN) is not more than about 1.25 weight percentage of the composition,

Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than about 1 .0 weight percentage of the composition, and cesium is not more than 0.25 percentage of the composition. In some such embodiments, the composition is a lyophilized powder.

[0046] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, Ru ^m Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), Ru ^m Cl3(Hind)(HN=C(Me)ind), and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 30 to about 70 weight percent of the composition, mannitol is about 30 to about 70 weight percent of the composition, citric acid is about 0.001 to about 1 weight percent of the composition, sodium citrate is about 0.0001 to about 1 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than about 0.5 weight percentage of the composition,

Ru ^m Cl3(Hind)2(CH3CN) is not more than about 1.25 weight percentage of the composition,

Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than about 1 .0 weight percentage of the composition, and cesium is not more than 0.25 percentage of the composition. In some such embodiments, the composition is a lyophilized powder.

[0047] Compositions are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, Ru ^m Cl3(Hind)2(H20), Ru ^IN Cl3(Hind)2(CH3CN), Ru ^m Cl3(Hind)(HN=C(Me)ind), and cesium, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease; wherein: sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)] is about 20 to about 80 weight percent of the composition, mannitol is about 20 to about 80 weight percent of the composition, citric acid is about 0.0001 to about 5 weight percent of the composition, sodium citrate is about 0.00001 to about 5 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than about 0.5 weight percentage of the composition,

Ru ^m Cl3(Hind)2(CH3CN) is not more than about 1.25 weight percentage of the composition,

Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than about 1.0 weight percentage of the composition, and cesium is not more than 0.25 percentage of the composition. In some such embodiments, the composition is a lyophilized powder.

[0048] Unit dosage forms are provided, comprising a formulation or composition described herein. The expression "unit dosage form" as used herein refers to a physically discrete unit of a provided formulation appropriate for the subject to be treated. It will be understood, however, that the total daily usage of provided formulation will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active agent employed; specific formulation employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active agent employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.

[0049] Compositions described herein can accordingly be provided as a unit dosage form. In some embodiments, a vial comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate is a unit dosage form, for use in treating a coronavirus disease caused by a coronavirus, or for use in formulating a medicament for treating such a disease.

[0050] Vials are accordingly provided, comprising sodium trans- [tetrachlorobis(1 H-indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, and cesium is a unit dosage form.

[0051] Vials may also be provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate, Ru ^m Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), Ru ^m Cl3(Hind)(HN=C(Me)ind),and cesium is a unit dosage form. [0052] Pharmaceutical packs and/or kits are provided, comprising compositions described herein, or a unit dosage form comprising a provided composition, and a container (e.g., a foil or plastic package, or other suitable container). Optionally instructions for use are additionally provided in such kits.

[0053] Unit dosage forms may for example take the form of a vial comprising sodium frans-[tetrachlorobis(1 H-indazole)ruthenate (III)], mannitol, citric acid, sodium citrate is a unit dosage form depicted in Table 1

Table 1: Pharmaceutical Components

[0054] The pharmaceutical components described in Table 1 may further comprise cesium; wherein: cesium is not more than 0.25 weight percentage of the composition. [0055] The pharmaceutical components described in Table 1 may further comprise cesium, Ru ^IN Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), and Ru ^m Cl3(Hind)(HN=C(Me)ind); wherein: cesium is not more than about 0.25 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than about 0.5 weight percentage of the composition,

Ru ^IN Cl3(Hind)2(CH3CN) is not more than about 1.25 weight percentage of the composition, and Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than about 1.0 weight percentage of the composition.

[0056] Pharmaceutical compositions may be comprised of components selected from those in Table 2:

Table 2: Pharmaceutical Component Ranges

[0057] The pharmaceutical components described in Table 2 may further comprise cesium; for example wherein cesium is not more than 0.25 weight percentage of the composition.

[0058] The pharmaceutical components described in Table 2 may further comprise cesium, Ru ^IN Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), and Ru ^m Cl3(Hind)(HN=C(Me)ind); wherein: cesium is not more than about 0.25 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than about 0.5 weight percentage of the composition,

Ru ^m Cl3(Hind)2(CH3CN) is not more than about 1.25 weight percentage of the composition, and Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than about 1.0 weight percentage of the composition.

[0059] Vials are provided comprising sodium frans-[tetrachlorobis(1 H- indazole)ruthenate (III)], mannitol, citric acid, sodium citrate in a unit dosage form depicted in Table 3:

Table 3: Pharmaceutical Components

[0060] The pharmaceutical components described in Table 3 may further comprise cesium; for example wherein cesium is not more than 0.25 weight percentage of the composition.

[0061] The pharmaceutical components described in Table 3 may further comprise cesium, Ru ^IN Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), and Ru ^m Cl3(Hind)(HN=C(Me)ind); wherein: cesium is not more than about 0.25 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than about 0.5 weight percentage of the composition,

Ru ^IN Cl3(Hind)2(CH3CN) is not more than about 1.25 weight percentage of the composition, and Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than about 1.0 weight percentage of the composition.

[0062] Pharmaceutical compositions are provided having components selected from those in Table 4:

Table 4: Pharmaceutical Components

[0063] The pharmaceutical components described in Table 4 may further comprise cesium; for example wherein cesium is not more than 0.25 weight percentage of the composition.

[0064] The pharmaceutical components described in Table 4 may further comprise cesium, Ru ^IN Cl3(Hind)2(H20), Ru ^m Cl3(Hind)2(CH3CN), and Ru ^m Cl3(Hind)(HN=C(Me)ind); wherein: cesium is not more than about 0.25 weight percentage of the composition, Ru ^IN Cl3(Hind)2(H20) is not more than about 0.5 weight percentage of the composition,

Ru ^m Cl3(Hind)2(CH3CN) is not more than about 1.25 weight percentage of the composition, and Ru ^m Cl3(Hind)(HN=C(Me)ind) is not more than about 1.0 weight percentage of the composition.

[0065] The pharmaceutical components may for example comprise cesium present in an amount of about 0.001 , 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.015, 0.020, 0.025, 0.030, 0.035, 0.040, 0.045, 0.050, 0.055, 0.060, 0.065, 0.070, 0.075, 0.080, 0.085, 0.090, 0.095, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, or 1.0 weight percentage of the composition.

[0066] Methods are provided for prophylactically or therapeutically treating a coronavirus disease caused by a coronavirus (Coronaviridae) in a subject in need thereof, comprising administering to the subject a composition comprising BOLD-100, having components as described above and herein. Methods are also provided for treating a coronavirus disease caused by a coronavirus by reducing the amount of GRP78 in cells of a subject following administration of BOLD-100. The subject may be a human patient. [0067] Diseases caused by a variety of coronaviruses may be treated, in addition to SARS-CoV-2, for example: human coronavirus 229E, OC43, NL63, orHKUI; SARS-CoV; Middle East respiratory syndrome coronavirus; porcine transmissible gastroenteritis coronavirus; bovine coronavirus; feline coronavirus; canine coronavirus; turkey coronavirus and pantropic canine coronavirus.

[0068] Variants of the SARS-CoV-2 virus may be treated, for example variants classified as Variants of Interest or Variants of Concern, as for example listed in Table 5 and Table 6.

Table 5: Selected SARS-CoV-2 Variants of Interest

Name

(Pango Name lineage) Substitution (Nextstrain)

Spike: (L5F*), T95I, D253G, 20C

(S477N*), (E484K*), D614G,

(A701V*)

ORF1a: L3201P, T265I, D3675/3677 ORF1b: P314L, Q1011H ORF3a: P42L, Q57H ORF8: T111

B.1.526 5’UTR: R81C

Spike: A67V, D69/70, D144, E484K, 20C D614G, Q677H, F888L ORF1b: P314F ORF1a: T2007I M: I82T

N: A12G, T205I B.1.525 5’UTR: R81C

Spike: E484K, D614G, V1176F 20J

ORF1a: L3468V, L3930F ORF1b: P314L

N: A119S, R203K, G204R, M234I

P.2 5’UTR: R81C

(*)=detected in some sequences but not all Table 6: Selected SARS-CoV-2 Variants of Concern

Name

(Pango Spike Protein Name BEI Reference lineage) Substitutions (Nextstrain) | _so | _a te

D69/70 20I/501Y.V1 NR-54000

D144U

(E484K ^* )

(S494P ^* )

N501Y

A570D

D614G

B.1.1.7 P681 H

K417N/T 20J/501 Y.V3 NR-54982

E484K

N501Y

P.1 D614G

K417N 20H/501.V2 NR-54009

E484K

N501Y

B.1.351 D614G

L452R 20C/S:452R

B.1.427 D614G

S13I 20C/S:452R

W152C

L452R

B.1.429 D614G

( ^* )=detected in some sequences but not all

[0069] Methods are also provided for treating a viral disease caused by a virus other than a coronavirus, for example by reducing the amount of GRP78 in cells, for example the virus may be one of Adenoviridae, Herpesviridae, Papillomaviridae, Polyomaviridae, Poxviridae, Hepadnaviridae, Parvoviridae, Astroviridae, Caliciviridae, Picornaviridae, Flaviviridae, Togaviridae, Retroviridae, Orthomyxoviridae, Arenaviridae, Bunyaviridaem, Filoviridae, Paramyxoviridae, Rhabdoviridae, Reoviridae, Arteriviridae, Asfarviridae; Circoviridae, and Flepeviridae. In some embodiments, the virus can be one or more of: Adenovirus, Flerpes simplex, type 1 , Flerpes simplex, type 2, Varicella-zoster virus, Epstein-barr virus, Fluman cytomegalovirus, Human herpesvirus, type 8, Human papillomavirus, BK virus, JC virus, Smallpox, Hepatitis B virus, Human bocavirus, Parvovirus B19, Human astrovirus, Norwalk virus, coxsackievirus, hepatitis A virus, poliovirus, rhinovirus, Severe acute respiratory syndrome virus, Hepatitis C virus, yellow fever virus, Hepatitis E virus, and Human immunodeficiency virus (HIV), Ebola virus, Marburg virus, Zika virus, Dengue virus, Japanese encephalitis virus, St. Louis encephalitis, West Nile virus, tick-borne encephalitis virus, Hepatitis C virus, Influenza A, Influenza B, Influenza C, avian influenza, swine influenza, measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus, coxsackie virus, rabies virus and vesicular stomatitis virus and rubella virus.

[0070] The viral infection, for example a coronavirus infection (such as SARS-CoV-2), may be of a specific organ or tissue, for example an infection of the lung, pharynx, trachea, blood, heart, vessels, intestines, brain, male genitals and/or kidneys), or a viral infection that is detectable in body fluids, such as mucus, saliva, urine, cerebrospinal fluid, semen and/or breast milk.

[0071] A titratable dosage may for example be adapted to allow a patient to take the medication in doses smaller than the unit dose, wherein a "unit dose" is defined as the maximum dose of medication that can be taken at any one time or within a specific dosage period. Titration of doses will allow different patients to incrementally increase the dose until they feel that the medication is efficacious, as not all patients will require the same dose to achieve the same benefits. A person with a larger build or faster metabolism may require larger doses to achieve the same effect as another with a smaller build or slower metabolism. Therefore, a titratable dosage has advantages over a standard dosage form. [0072] Formulations may be adapted to be delivered in such a way as to target one or more of the following: sublingual, buccal, oral, rectal, nasal, parenteral and via the pulmonary system. Formulations may for example be in one or more of the following forms: gel, gel spray, tablet, liquid, capsule, by injection, or for vaporization.

[0073] Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the formulations to subjects. Routes of administration may for example include, parenteral, intravenous, intradermal, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intrathecal, intracisternal, intraperitoneal, intranasal, inhalational, aerosol, topical, sublingual or oral administration. Therapeutic formulations may be in the form of liquid solutions or suspensions; for oral administration, formulations may be in the form of tablets or capsules; for intranasal formulations, in the form of powders, nasal drops, or aerosols; and for sublingual formulations, in the form of drops, aerosols or tablets.

[0074] Methods well known in the art for making formulations are found in, for example, “Remington: The Science and Practice of Pharmacy” (21st edition), ed. David Troy, 2006, Lippincott Williams & Wilkins. Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.

[0075] Pharmaceutical compositions may be in any form which allows for the composition to be administered to a patient. For example, the composition may be in the form of a solid, liquid or gas (aerosol). Pharmaceutical composition of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a patient may take the form of one or more dosage units, where for example, a tablet, capsule or cachet may be a single dosage unit, and a container of the compound in aerosol form may hold a plurality of dosage units.

[0076] Materials used in preparing the pharmaceutical compositions should be pharmaceutically pure and non-toxic in the amounts used. The present compositions may include one or more compounds (active ingredients) known for a particularly desirable effect. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the particular form of the active ingredient, the manner of administration and the composition employed.

[0077] In general, the pharmaceutical composition includes a formulation of BOLD- 100, in admixture with one or more carriers. The carrier(s) may be particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup or injectable liquid. In addition, the carrier(s) may be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory administration.

[0078] When intended for oral administration, the composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

[0079] As a solid formulation for oral administration, the composition may be formulated into a powder, granule, compressed tablet, pill, capsule, cachet, chewing gum, wafer, lozenges, or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following adjuvants may be present: binders such as syrups, acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin, and mixtures thereof; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; fillers such as lactose, mannitols, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof; lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, wetting agents such as sodium lauryl sulfate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent. When the composition is in the form of a capsule, e.g., a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil.

[0080] The formulation may be in the form of a liquid, e.g., an elixir, syrup, solution, aqueous or oily emulsion or suspension, or even dry powders which may be reconstituted with water and/or other liquid media prior to use. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, compositions may contain, in addition to the present compounds, one or more of a sweetening agent, thickening agent, preservative (e.g., alkyl p-hydoxy benzoate), dye/colorant and flavor enhancer (flavorant). In a composition intended to be administered by injection, one or more of a surfactant, preservative (e.g., alkyl p- hydroxybenzoate), wetting agent, dispersing agent, suspending agent (e.g., sorbitol, glucose, or other sugar syrups), buffer, stabilizer and isotonic agent may be included. The emulsifying agent may be selected from lecithin or sorbitol monooleate.

[0081] The liquid pharmaceutical formulations of the invention, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a possible adjuvant. An injectable pharmaceutical composition is preferably sterile. [0082] The pharmaceutical formulation may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment, cream or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

[0083] The formulation may be intended for rectal administration, in the form, e.g., of a suppository which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter and polyethylene glycol. Low- melting waxes are available for the preparation of a suppository, where mixtures of fatty acid glycerides and/or cocoa butter are suitable waxes. The waxes may be melted, and the aminocyclohexyl ether compound is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0084] The formulation may include various materials which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials which form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule or cachet.

[0085] The pharmaceutical formulation may consist of or comprise gaseous dosage units, e.g., it may be in the form of an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems comprising pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system which dispenses the active ingredients. Aerosols of compounds of the invention may be delivered in single phase, bi-phasic, or tri-phasic systems in order to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, and the like, which together may form a kit.

[0086] Some biologically active compounds may be in the form of the free base or in the form of a pharmaceutically acceptable salt such as the hydrochloride, sulfate, phosphate, citrate, fumarate, methanesulfonate, acetate, tartrate, maleate, lactate, mandelate, salicylate, succinate and other salts known in the art. The appropriate salt would be chosen to enhance bioavailability or stability of the compound for the appropriate mode of employment (e.g., oral or parenteral routes of administration). [0087] The present invention also provides kits that contain a pharmaceutical formulation, together with instructions for the use of the formulation. Preferably, a commercial package will contain one or more unit doses of the formulation. Formulations which are light and/or air sensitive may require special packaging and/or formulation. For example, packaging may be used which is opaque to light, and/or sealed from contact with ambient air, and/or formulated with suitable coatings or excipients.

[0088] The formulations of the invention can be provided alone or in combination with other compounds (for example, small molecules, nucleic acid molecules, peptides, or peptide analogues), in the presence of a carrier or any pharmaceutically or biologically acceptable carrier. As used herein “pharmaceutically acceptable carrier” or “excipient” includes any and all suitable solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The carrier can be suitable for any appropriate form of administration. Pharmaceutically acceptable carriers generally include sterile aqueous solutions or dispersions and sterile powders. Supplementary active compounds can also be incorporated into the formulations.

[0089] An “effective amount” of a formulation according to the invention includes a therapeutically effective amount or a prophylactically effective amount. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a formulation may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount may also be one in which any toxic or detrimental effects of the formulation or active compound are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount. For any particular subject, the timing and dose of treatments may be adjusted over time ( e.g timing may be daily, every other day, weekly, monthly) according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

EXAMPLE 1 : Antiviral Efficacy

[0090] The antiviral activity of sodium trans-[tetrachloridobis(1 H- indazole)ruthenate(lll)] (BOLD-100) was illustrated using SARS-CoV-2 (Wuhan strain) in an in vitro cytopathic effect (CPE) assay. Vero-E6 monkey kidney epithelial cells were used, an established standard cell line for antiviral testing, with SARS-CoV-2 2019- nCoV/USA-WA-1/2020 (isolated from a patient in the USA who returned from Wuhan China with the disease). BOLD-100 had cytotoxic effects on these cells in the 200 to 400mM range. Vero-E6 cells were infected with SARS-CoV-2 (MOI=0.01 ) in quadruplicate for 2 hours and then incubated with varying concentrations of BOLD-100 for 3 days. Cell death as a result of viral replication was measured using the cytopathic effect assay. Non linear regression analysis was performed using three parameter dose response to determine the relative ICso and absolute ECso values.

[0091] In post infection treatments, Vero-E6 cells were infected by the SARS-CoV-2 (Wuhan strain) with a multiplicity of infection (MOI) of 0.01. After 2 hours, the virus was washed off and new media supplied. Cell survival was then measured after 3 days. As shown in Figure 1, a relative ICso of 9.4 nM and an absolute ECso of 1.8 mM was determined for BOLD-100.

[0092] In pre-infection treatments, Vero-E6 cells were treated with BOLD-100 for 3 hours. The cells were then infected by SARS-CoV-2 (Wuhan strain) with an MOI of 0.01 . After 2 hours, the virus was washed off and new media supplied including BOLD-100. Cell survival was then measured after 3 days. A relative ICso of 15.6 nM and an absolute ECso of 1.9 pM was determined for BOLD-100. Similar results were obtained in parallel assays using an MOI of 0.02.

[0093] These results illustrate both pre and post-infection coronavirus antiviral efficacy for BOLD-100, in a SARS-CoV-2 in vitro model of antiviral efficacy, with nanomolar inhibition of viral replication in cell culture (relative ICso) and a 50% reduction in viral cell death at low micromolar concentrations (absolute ECso), far below cytotoxic concentrations of BOLD-100.

EXAMPLE 2: Remdesivir Comparator

[0094] This Example illustrates the relative antiviral efficacy of BOLD-100, using as a comparator the established antiviral Remdesivir ((2S)-2-{(2R,3S,4R,5R)-[5-(4- Aminopyrrolo[2,1- ] [1 ,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxy-tetrahydro-furan-2- ylmethoxy]phenoxy-(S)-phosphorylamino}propionic acid 2-ethyl-butyl ester). The protocol for this Example is as set out in Example 1 , with antiviral activity illustrated using SARS-CoV-2 (Wuhan isolate) in an in vitro cytopathic effect (CPE) assay with Vero-E6 monkey kidney epithelial cells. In accordance with that protocol, Vero-E6 cells where incubated with varying concentrations of BOLD-100 or Remdesivir for 48 or 72 hours, and the degree of cell survival was measured.

[0095] The data reflected in Figure 2 was obtained by infecting Vero-E6 cells with SARS-CoV-2 at an MOI of 0.01, then BOLD-100 or Remdesivir were independently added at multiple concentrations and cell survival was measured at 48 or 72 hours. These results accordingly illustrate the relative antiviral efficacy of BOLD-100 and Remdesivir in post infection treatments, assessed at 48 and 72 hours. At both 48 and 72 hours, BOLD-100 had low nanomolar ICso antiviral activity that was significantly lower than the parallel experiments with Remdesivir.

[0096] The data reflected in Figure 3 was obtained by treating Vero-E6 cells with then BOLD-100 or Remdesivir at multiple concentrations for a 1 hour pre-treatment, then infecting the pre-treated cells with SARS-CoV-2 at an MOI of 0.01 , and measuring cell survival at 48 or 72 hours. In these pre-treatment models, the cells are exposed throughout the entire experiment to BOLD-100 or remdesivir, in effect the treatment is identical to the post treatment models, but with an addition of 1 hour of pre-treatment. These results accordingly illustrate the relative antiviral efficacy of BOLD-100 and Remdesivir in pre-infection treatments, assessed at 48 and 72 hours. At both 48 and 72 hours, BOLD-100 had low nanomolar ICso antiviral activity that was significantly lower than the parallel experiments with Remdesivir. [0097] The nanomolar efficacy of BOLD-100 in the coronavirus models disclosed herein, particularly in comparison to the lesser activity of the established antiviral agent remdesivir, evidence a general utility of BOLD-100 in therapeutically or prophylactically treating viral infections.

EXAMPLE 3: 293T protein and RNA levels

[0098] As illustrated in Figures 4A and 4B, in a human cell line (embryonic kidney 293T-ACE2 cells) measurements of SARS-CoV-2 (strain 2019-nCoV/USA-WA-1/2020) viral nucleocapsid RNA and protein levels provide a clear indication of dose-dependant inhibition of viral replication/production by BOLD-100. This data was obtained as follows. In post infection treatments, human kidney 293T-ACE2 cells were infected by SARS-CoV-2 (2019-nCoV/USA-WA-1/2020) with a multiplicity of infection (MOI) of 0.001. After 1 hour, the virus was washed off and new media supplied. Cell lysates were harvested 48 hours post-infection. Viral nucleocapsid RNA levels in cell lysates were measured by quantitative RT-PCR and viral nucleocapsid protein levels were measured by western blot with GAPDH as an internal control. As shown in Figure 4B, an IC50 of 40.50 mM was determined for reduced viral RNA levels.

EXAMPLE 4: 293T viral release supernatant

[0099] Using a protocol as described for Example 5, but assaying the supernatant of a cell pellet as an indication of viral release, a clear dose-dependent inhibition of viral release by BOLD-100 is illustrated in Figure 5. This data was obtained as follows. Human kidney 293T-ACE2 cells were plated in a 96-well plate at a density of 15,000 cells per well. The following day, cells were infected with SARS-CoV-2 (wildtype strain) for 2 hours. The virus was then removed and replaced with fresh media containing various concentrations of BOLD-100. Cells were incubated for 48 hours then virus released into the supernatant was harvested, viral RNA extracted and then virus levels were measured using Taqman qRT-PCR.

EXAMPLE 5: California (UK) variant [00100] As illustrated in Figure 6, BOLD-100 is effective in treating a COVID-19 variant of concern, the California version of the B.1.1.7 (UK). The micrographs of Figure 6 show clear prevention of cellular death at 200uM BOLD-100. This data was obtained as follows. 15,000 human kidney 293T-ACE2 cells were plated in a 96-well plate overnight. The following day, some cells were infected with a SARS-CoV-2 variant (MOI= 0.001) (SARS-CoV-2 Isolate hCoV-19/USA/CA_CDC_5574/2020- B.1.1.7 variant: isolated from a nasopharyngeal swab collected on December 29, 2020 in San Diego County, California, USA) for 48 hours. Brightfield images were obtained using an EVOS M7000 imaging system (Thermo Fisher Scientific). Six independent and adjacent images were taken at the center of each well and stitched together using ImageJ.

(M2.1.0/1 53c). Some cells were treated with 200mM BOLD-100 for the duration of the experiment.

EXAMPLE 6: A549 cells

[00101] As illustrated in Figure 7, BOLD-100 is effective in treating a SARS-CoV-2 infection in lung cells. This data was obtained as follows. A549-ACE2 cells were plated in a 96-well plate at a density of 15,000 cells per well. The following day, cells were infected with SARS-CoV-2 (wildtype strain) for 2 hours (MOI=0.04). The virus was then removed and replaced with fresh media containing various concentrations of BOLD- 100. Cells were incubated for 48 hours then virus released into the supernatant was harvested, viral RNA extracted and then virus levels were measured using Taqman qRT-PCR.

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[00128] Citation of references herein is not an admission that such references are prior art to the present invention. Any priority document(s) and all publications, including but not limited to patents and patent applications, cited in this specification, and all documents cited in such documents and publications, are hereby incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Terms such as “exemplary” or “exemplified” are used herein to mean “serving as an example, instance, or illustration.” Any implementation described herein as “exemplary” or “exemplified” is accordingly not to be construed as necessarily preferred or advantageous over other implementations, all such implementations being independent embodiments. Unless otherwise stated, numeric ranges are inclusive of the numbers defining the range, and numbers are necessarily approximations to the given decimal. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

[00129] In some embodiments, the invention excludes steps that involve medical or surgical treatment.