CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Application No. 17/572,215, filed January 10, 2022. The entire disclosure of the above application is incorporated herein by reference.

FIELD

[0002] The present disclosure generally relates to a diagnostic and treatment of microbial infections, particularly infections from the coronavirus.

BACKGROUND

[0003] This section provides background information related to the present disclosure which is not necessarily prior art.

[0004] The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified in 2019 and has since spread across the world. It is present in every virtually country and has been declared a pandemic by the World Health Organization (WHO). Those infected with SARS-CoV-2 may develop coronavirus disease (CO VID-19). Due to its rapid expansion, humans have yet to develop a natural herd immunity to the virus. Although three vaccines have been approved in the United States to combat SARS-CoV-2, treatment options remain limited. Current treatments include monoclonal antibody treatments (e.g., casirivimab and imdevimab), antivirals (e.g., remdesivir), immunomodulators (e.g., dexamethasone), oxygenation, ventilation, and supportive care.

[0005] SARS-CoV-2 is rapidly becoming endemic: a major nuisance virus that will continue to cause local and global disruptions. Variants appear every four to six months. Omicron, the latest variant, is breaking through existing vaccines and ravaging the unvaccinated. Clearly, vaccines alone will not halt the outbreak of variants and antibody therapy is of limited clinical use. The persistence of SARS-CoV-2, and COVID- 19, causes severe social and economic costs in the trillions of dollars per year. The need for oral antiviral therapeutics is evident. Such therapeutics will be critical for suppressing outbreaks, reducing community spread, and treating the unvaccinated. Successful management of COVID- 19 will reduce the social fear of returning to work and travel and allow the time for proper rollout of vaccine programs in developing nations. [0006] Current treatments are insufficient. Molnupiravir is not particularly effective for treating SARS-CoV-2 and is mutagenic. Paxlovid® (nirmatrelvir), and other protease inhibitors, appear effective for treating SARS-CoV-2 infections but have significant drug interactions with medications taken by vulnerable populations. Remdesivir has only a conditional recommendation from the World Health Organization for treating COVID-19.

[0007] Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase and is sold under brand names such as Avigan, Avifavir, Areplivir, FabiFlu, Favipira, Qifenda, and Reeqonus. In vivo, favipiravir is phosphorylated to its active form, favipiravir-RTP. Favipiravir and favipiravir-RTP are known to be effective against influenza viruses, arenaviruses, bunyaviruses, and filoviruses. (Furuta, et iPProc Jpn Acad Ser B Phys Biol Sci, 2017.) Favipiravir’ s effect on SARS-CoV-2 or its efficacy for treating COVID-19 remains undetermined. (Hassanipour, et al., Sci Rep., 2021.)

SUMMARY

[0008] This section provides a general summary of the disclosure, and is not a comprehensive disclosure of its full scope or all of its features.

[0009] One embodiment described herein is a method for treating early-stage infection by a microbe, such as a virus, comprising the steps of obtaining a sample from a subject, providing the sample to a lateral flow assay, determining whether the subject is infected with the microbe, and, if the subject is so infected, treating the subject with an antimicrobial agent, such as an antiviral agent, and a cathepsin inhibitor. In some embodiments, the subject has been exposed to the virus, is suspected of having been exposed to the virus, or has been in contact with a person exposed to or suspected of being exposed to the virus.

[0010] In another embodiment described herein is a method for treating a subject having an early-stage viral infection comprising administering to the subject an antiviral agent and a cathepsin inhibitor.

DETAILED DESCRIPTION

[0011] The description included herein are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure.

I. Definitions [0012] At the outset, in the context of the present disclosure, the following is provided for reference with regard to various terms and/or abbreviations and/or descriptions herein.

[0013] As used herein, the term “microbe” refers to one or more organisms that infect a body and may cause illness. Microbes are generally known in the art and include viruses, bacteria, fungus, and parasites. Viruses include the family of coronaviruses, which includes SARS-CoV- 2, which is responsible for CO VID- 19, as well as Alphacoronavirus 1 (TGEV, Feline coronavirus, Canine coronavirus), Human coronavirus 229E, Human coronavirus NL63, Miniopterus bat coronavirus 1, Miniopterus bat coronavirus HKU8, Porcine epidemic diarrhea virus, Rhinolophus bat coronavirus HKU2, Scotophilus bat coronavirus 512, Betacoronavirus 1 (Bovine Coronavirus, Human coronavirus OC43), Hedgehog coronavirus 1, Human coronavirus HKU1, Middle East respiratory syndrome-related coronavirus, Murine coronavirus, Pipistrellus bat coronavirus HKU5, Rousettus bat coronavirus HKU9, Tylonycteris bat coronavirus HKU4, Avian coronavirus, Beluga whale coronavirus SW1, Bulbul coronavirus HKU11, or Porcine coronavirus HKU15. Additional viruses include, but are not limited to, arenaviruses (e.g., Guanarito virus, Junin virus, Lassa virus, Lujo virus, Machupo virus, Sabia virus, or Whitewater Arroyo virus); phleboviruses (e.g., Alenquer phlebovirus, Bhanja virus, Candiru phlebovirus, Chagres virus, Sandfly fever Naples phlebovirus, Punta Toro phlebovirus, Rift Valley fever virus, Sicilian phlebovirus, Toscana phlebovirus, Uukuniemi virus, or Heartland bandavirus); hantaviruses (e.g., Andes orthohantavirus, Asama orthohantavirus, Asikkala orthohantavirus, Bayou orthohantavirus, Black Creek Canal orthohantavirus, Bowe orthohantavirus, Bruges orthohantavirus, Cano Delgadito orthohantavirus, Cao Bang orthohantavirus, Choclo orthohantavirus, Dabieshan orthohantavirus, Dobrava-Belgrade orthohantavirus, El Moro Canyon orthohantavirus, Fugong orthohantavirus, Fusong orthohantavirus, Hantaan orthohantavirus, Jeju orthohantavirus, Kenkeme orthohantavirus, Khabarovsk orthohantavirus, Laguna Negra orthohantavirus, Luxi orthohantavirus, Maporal orthohantavirus, Montano orthohantavirus, Necocli orthohantavirus, Oxbow orthohantavirus, Prospect Hill orthohantavirus, Puumala orthohantavirus, Robina orthohantavirus, Rockport orthohantavirus, Sangassou orthohantavirus, Seewis orhtohantavirus, Seoul orthohantavirus, Sin Nombre orthohantavirus, Tatenale orthohantavirus, Thailand orthohantavirus, Tigray orthohantavirus, Tula orthohantavirus, or Yakeshi orthohantavirus); flavivirus (e.g., Apoi virus, Aroa virus, Bagaza virus, Banzi virus, Bouboui virus, Bukalasa bat virus, Cacipacore virus, Carey Island virus, Cowbone Ridge virus, Dakar bat virus, Dengue virus, Edge Hill virus, Entebbe bat virus, Gadgets Gully virus, Ilheus virus, Israel turkey meningoencephalomyelitis virus, Japanese encephalitis virus, Jugra virus, Jutiapa virus, Kadam virus, Kedougou virus, Kokobera virus, Koutango virus, Kyasanur Forest disease virus, Langat virus, Louping ill virus, Meaban virus, Modoc virus, Montana myotis leukoencephalitis virus, Murray Valley encephalitis virus, Ntaya virus, Omsk hemorrhagic fever virus, Phnom Penh bat virus, Powassan virus, Rio Bravo virus, Royal Farm virus, Saboya virus, Saint Louis encephalitis virus, Sal Vieja virus, San Perlita virus, Saumarez Reef virus, Sepik virus, Tembusu virus, Tick-borne encephalitis virus, Tyuleniy virus, Uganda S virus, Usutu virus, Wesselsbron virus, West Nile virus, Yaounde virus, Yellow fever virus, Yokose virus, or Zika virus); enterovirus (e.g., poliovirus, coxsackie A virus, coxsackie B viruses, rhinoviruses, or echoviruses); alphaviruses (e.g., Aura virus, Barmah Forest virus, Bebaru virus, Caaingua virus, Cabassou virus, Chikungunya virus, Eastern equine encephalitis virus, Eilat virus, Everglades virus, Fort Morgan virus, Getah virus, Highlands J virus, Madariaga virus, Mayaro virus, Middelburg virus, Mosso das Pedras virus, Mucambo virus, Ndumu virus, O'nyong'nyong virus, Pixuna virus, Rio Negro virus, Ross River virus, Salmon pancreas disease virus, Semliki Forest virus, Sindbis virus, Southern elephant seal virus, Tonate virus, Trocara virus, Una virus, Venezuelan equine encephalitis virus, Western equine encephalitis virus, or Whataroa virus); paramyxoviruses (e.g., mumps virus, measles virus, human parainfluenza viruses, hendra virus, nipah virus); norovirus (e.g., Norwalk virus, Desert Shield virus, Southampton virus, Bristol virus, Lordsdale virus, Toronto virus, Mexico virus, Hawaii virus, or Snow Mountain virus); respiratory syncytial virus; influenza virus; severe fever with thrombocytopenia syndrome (SFTS) virus; and ebola virus.

[0014] As used herein, the term “antimicrobial agent” refers to compound or composition which is effective in killing, inhibiting the replication of, inhibiting infectivity of, and/or inhibiting the growth of one or more microbes. The antimicrobial agent includes antiviral agents, antibacterial agents (e.g., antibiotics), antiparasitic agents, and antifungal agents. Antiviral agents described herein are not particularly limited and include agents effective in killing and/or inhibiting the replication, infectivity, and/or growth of one or more viruses. Antiviral drugs of the present disclosure may be, for example, 5-substituted 2'-deoxyuridine analogues nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, viral protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogues, acyclic nucleoside, and/or phosphonate analogues. The antiviral agent may be a purine nucleic acid analog, such as an inhibitor of RNA-dependent RNA polymerase (RDRP). Antiviral agents include, but are not limited to, favipiravir (T705, 6-fluoro-3-hydroxy- 2-pyrazinecarboxamide, or 5-fluoro-2-oxo-lH-pyrazine-3-carboxamide), favipiravir-RTP (the ribofuranosyl-5 ’ -triphosphate derivative of favipiravir), remdesivir (GS-5734; L- Alanine, N- [(S)-hydroxyphenoxyphosphinyl]-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo[2,l- f][l,2,4]triazin-7-yl)-2,5-anhydro-D-altrononitrile), and molnupiravir (MK-4482/EIDD-2801; P- D-N4-Hydroxycytidine-5 '-isopropyl ester).

[0015] Antibacterial agents described herein are not particularly limited and include agents effective in killing and/or inhibiting the replication, infectivity, and/or growth of one or more bacteria. Antibacterial agents include, but are not limited to, amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole and trimethoprim, amoxicillin and clavulanate, levofloxacin, and azithromycin.

[0016] Antiparasitic agents described herein are not particularly limited and include agents effective in killing and/or inhibiting the reproduction, growth, or infectivity of one or more parasites. The antiparasitic agent includes avermectins, which are compounds comprising a 16- membered macrocyclic lactone. Avermectins include ivermectin, selamectin, doramectin, eprinomectin, and abamectin. Alternatively, the antiparasitic agent includes nitazoxanide, melarsoprol, eflornithine, metronidazole, tinidazole, miltefosine, mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, niclosamide, praziquantel, albendazole, praziquantel, rifampin, amphotericin B, and fumagillin.

[0017] Antifungal agents described herein are not particularly limited and include agents effective in killing and/or inhibiting the replication, infectivity, and/or growth of one or more fungi. Antifungal agents include, but are not limited to, clotrimazole, econazole, miconazole, terbinafine, fluconazole, ketoconazole, nystatin, amphotericin, and ketoconazole.

[0018] As used herein, the term “combination” refers to an association of two or more active agents. As used herein, a combination comprises an antiviral agent and a cathepsin inhibitor. Combination encompasses separate formulations, such as where the antiviral agent and the cathepsin inhibitor are provided in separate dosage forms, such as in a kit. Alternatively, the combination encompasses a single formulation, such as when the antiviral agent and the cathepsin inhibitor are provided in a single composition, including but not limited to, a tablet, capsule, caplet, solution, suspension, and emulsion.

[0019] As used herein, “cathepsin inhibitor” refers to agents that inhibit or otherwise block the activity of a cathepsin. Cathepsins are proteases classified, in part, by the location at which they cleave proteins or peptides. For examples, cathepsins A and G are serine proteases; cathepsins B, C, F, H, K, E (Fl), O, S, V (L2), W, and Z (X) are cysteine proteases; cathepsins D and E are aspartyl proteases. A cathepsin inhibitor may be a cathepsin-B inhibitor, a cathepsin-C inhibitor, a cathepsin-F inhibitor, a cathepsin-H inhibitor, a cathepsin-K inhibitor, a cathepsin- L inhibitor, a cathepsin-0 inhibitor, a cathepsin-S inhibitor, a cathepsin-V inhibitor, a cathepsin-W inhibitor, and a cathepsin-Z inhibitor. Specific cathepsin inhibitors include, but are not limited to, Balicatib (AAE581), Relacatib (GSK-462795, SB-462795), Odanacatib (MK-0822), SLV213 (K777 ORK1777), RO5459072, RWJ-445380, VBY036P1A, AM-3701, MIV-701,MIV-710, MIV-711,NC- 2300, ORG-219517, ONO-5334, MK-0674, GB-111-NH2, L-873724, L-006235, AZD4996, VBY-036, RWY-445380, AM-3840, Cz-007, VBY-825 (VBY-106; VBY-285;VBY- 825), VBY-129, SAR-114137, VBY-891, Petesicatib (RG-7625; RO-5459072), LY-3000328, MIV-247, CRA-028129, RG-7236, GSK2793660, Aloxistatin (E-64d, Loxistatin, EST), BI- 1181181 (VTP-37948), VBY-376, Aloxistatin (Ab-007; E-64-d), Begacestat (GSI-953; WAY- 210953), AL101 (BMS906024), BMS-986115 (AL-102), MK-0752 (L-000891675), EVP-0962 (EVP-0015962), BLD2660, SAR- 164653, KGP94, and VEL-0230. Examples of other cathepsin inhibitors are described in Dana et al., 2020. A Review of Small Molecule Inhibitors and Functional Probes of Human Cathepsin L. Molecules 25: 698. All references cited are herein incorporated in their entirety by reference thereto.

[0020] As used herein, the term “early-stage infection” refers to a stage of infection with a microbe wherein the subject does not present with symptoms associated with infection by the microbe. For example, a subject would be considered having an early-stage infection with SARS-CoV-2 after having been exposed to the virus but before presenting with symptoms associated with CO VID- 19 and/or a SARS-CoV-2 infection. The subject may be considered asymptomatic. Alternatively, a subject may be considered in an early-stage infection if the subject presents with symptoms of SARS-CoV-2 infection are indistinguishable from symptoms of infection from other microbes.

[0021] As used herein, a “lateral flow assay” refers to an assay that confirms the presence or absence of an analyte (e.g., an antigen of interest) in a sample, such as a biosample from a subject. The lateral flow assay is described in US 8,399,261, which is incorporated herein by reference. The antigen utilized in the lateral flow assay may be from a microbe, such as a virus (e.g., SARS-CoV-2) that has infected the subject.

[0022] As used herein, a “sample” refers to, for example, a biosample, obtained from the subject for use in the lateral flow assay. The sample is not particularly limited so long as it can be used in the lateral flow assay. The sample may be selected from the group consisting of saliva, blood, plasma, lymph, mucus, urine, feces, cells, and tissues.

[0023] As used herein, a “pharmaceutical composition” refers to a composition suitable for administration to a subject, such as a human, in a therapeutic and/or prophylactic capacity. The pharmaceutical composition comprises an antimicrobial agent, a cathepsin inhibitor, or both. In some embodiments, the pharmaceutical composition comprises both an antiviral agent, such as favipiravir, and a cathepsin inhibitor, such as balicatib or relacatib. The pharmaceutical agent may further comprise pharmaceutically acceptable excipients, including, but not limited to, binders, diluents, carriers, disintegrants, glidants, lubricants, colorants, sweeteners or flavoring agents, preservatives, antioxidants, fillers, emulsifiers, and surfactants. A “pharmaceutically acceptable” excipient refers to a compound or composition generally considered safe for pharmaceutical use, officially approved by a regulatory agency of a national or state government, or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, particularly humans.

[0024] As used herein, the term “treat” (and its corresponding terms “treatment” or “treating”) includes palliative and restorative treatment of a subject. The term “palliative treatment” refers to treatment that eases or reduces the effect or intensity of a condition in a subject without curing the condition. The term “restorative treatment” refers to treatment that halts the progression of, reduces the pathologic manifestations of, or entirely eliminates a condition (such as COVID-19 or SARS-CoV-2 infection) in a subject.

[0025] As used herein, “subject” may be used interchangeably with “individual” and “patient” and refers to a mammal, preferably a human or a non-human primate, but also includes domesticated mammals (e.g., canine or feline), laboratory mammals (e.g., mouse, rat, rabbit, hamster, or guinea pig), and agricultural animal (e.g., equine, bovine, porcine, or ovine). In certain embodiments, the subject can be human (e.g., adult male, adult female, adolescent male, adolescent female, male child, or female child) under the care of a physician or other health care worker. In other embodiments, the subject may not be under the care of a physician or other health care worker.

II. Compositions

[0026] A combination of an antimicrobial agent and a cathepsin inhibitor is provided herein.

The antimicrobial agent may be an antiviral agent. Alternatively, the antimicrobial agent may be an antibacterial agent, an antiparasitic agent, or an anti-fungal agent. In embodiments where the antimicrobial agent is an antiviral agent, the antiviral agent may be a purine nucleic acid analog and/or an RNA-dependent RNA polymerase inhibitor, including, but not limited to, favipiravir, favipiravir-RTP, remdesivir, and molnupiravir. In a preferred specific embodiment, the antiviral agent is favipiravir. In another embodiment, the cathepsin inhibitor a cathepsin K inhibitor. In a preferred specific embodiment, the cathepsin inhibitor may be balicatib or relacatib. Balicatib has a structure of formula I. Relacatib (also known as GSK-462795 or SB-462795) has a structure of formula II.

[0027] Formula I

[0028] Formula II

[0029] In a further embodiment, the antimicrobial agent (e.g., the antiviral agent) and the cathepsin inhibitor are provided in various doses. In an embodiment, the favipiravir is provided at a dose ranging between approximately 200 mg and approximately 3000 mg. The favipiravir may be delivered in a single daily dose (e.g., QD) or administered over multiple doses throughout the day, such as twice a day (e.g., BID), three times a day (e.g., TID), four times a day (e.g., QID), or more often. In a more particular embodiment, the favipiravir may be provided in a dose of between about 200 mg and about 1200 mg, between about 400 mg and about 1000 mg, between about 400 mg and about 800 mg, between about 600 mg and about 800 mg, between about 1200 mg and about 2400 mg, between about 1400 mg and about 2000 mg, or between about 1600 mg and about 1800 mg. Alternatively, the favipiravir may be administered at a dose of about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg. In embodiments where favipiravir may be provided multiple times, the amount of favipiravir administered to the subject may be the same or different.

[0030] In a further embodiment, balicatib may be provided of a dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, and about 100 mg. In embodiments where balicatib may be provided multiple times, the amount of balicatib administered to the subject may be the same or different. [0031] In a further embodiment, relacatib may be provided of a dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, and about 100 mg. In embodiments where relacatib may be provided multiple times, the amount of relacatib administered to the subject may be the same or different.

[0032] When used in combination any of the above-referenced doses of favipiravir may be combined with any of the above-referenced doses of balicatib. In a preferred embodiment, the dose of favipiravir may be between about 1600 mg and about 1800 mg and the dose of balicatib may be between about 10 and about 50 mg. In another preferred embodiment, the dose of favipiravir may be between about 400 mg and about 800 mg and the dose of balicatib may be between about 10 and about 50 mg.

[0033] When used in combination any of the above-referenced doses of favipiravir may be combined with any of the above-referenced doses of relacatib. In a preferred embodiment, the dose of favipiravir may be between about 1600 mg and about 1800 mg and the dose of relacatib may be between about 10 and about 50 mg. In another preferred embodiment, the dose of favipiravir may be between about 400 mg and about 800 mg and the dose of relacatib may be between about 10 and about 50 mg.

[0034] The antimicrobial agent (such as an antiviral agent) and the cathepsin inhibitor may be formulated in a single pharmaceutical composition. The antiviral agent may comprise at least 50% by weight of the total weight of the pharmaceutical composition. In such an embodiment, the cathepsin inhibitor may comprise less than 50% by weight of the total weight of the composition. Alternatively, the cathepsin inhibitor may comprise at least 50% by weight of the total weight of the pharmaceutical composition. In such an embodiment, the antiviral agent may comprise less than 50% by weight of the total weight of the pharmaceutical composition. As a specific example, the single pharmaceutical composition may comprise favipiravir at more than 50% by weight of the total weight of the composition and balicatib at less than 50% by weight of the total composition. As another specific example, the single pharmaceutical composition may comprise balicatib at more than 50% by weight of the total weight of the composition and favipiravir at less than 50% by weight of the total composition. As another specific example, the single pharmaceutical composition may comprise favipiravir at more than 50% by weight of the total weight of the composition and relacatib at less than 50% by weight of the total composition. As another specific example, the single pharmaceutical composition may comprise relacatib at more than 50% by weight of the total weight of the composition and favipiravir at less than 50% by weight of the total composition.

[0035] In an alternative embodiment, the antimicrobial agent (such as an antiviral agent) and the cathepsin inhibitor may be provided in separate formulations, such as in a kit. In such an embodiment, the separate formulations of the antimicrobial agent (such as an antiviral agent) and cathepsin inhibitor may be administered simultaneously, concurrently (e.g., with the antiviral agent administered immediately before or after the cathepsin inhibitor) or with a period of time between administrations. As a specific example, the antiviral agent may be favipiravir and the cathepsin inhibitor may be balicatib or relacatib.

[0036] Also provided is a combination of an antiviral agent and a cathepsin inhibitor wherein the combination is prepared by provided by combining at least one dose of the antiviral agent and at least one dose of the cathepsin inhibitor. The antiviral agent may be an RNA-dependent RNA polymerase inhibitor, including, but not limited to, favipiravir, favipiravir-RTP, remdesivir, and molnupiravir. The cathepsin inhibitor may be a cathepsin K inhibitor, such as balicatib or relacatib. The composition may be prepared by mixing favipiravir and balicatib, for example mixing the two drugs into a single composition. In a favipiravir-balicatib combination, the favipiravir may be provided at a dose of between about 1600 mg and 1800 mg or between about 400 mg and about 800 mg. The balicatib may be provided at a dose of between about 10 mg and about 50 mg.

II. Methods

[0037] In one embodiment is a method for treating an early- stage infection by a microbe in a subject, such as a virus, comprising the steps of obtaining a sample from the subject, providing the sample from the subject to a lateral flow assay, determining whether subject is infected with the microbe based on the results of the lateral flow assay, and if the subject is determined to be infected with the microbe, treating the subject with an antimicrobial agent and a cathepsin inhibitor, wherein the subject has been exposed to the microbe, is suspected of having been exposed to the microbe, or has been in contact with a person exposed to or suspected of being exposed to the microbe. In a particular embodiment, the microbe is a virus, such as a coronavirus. In a specific embodiment, the coronavirus is SARS-CoV-2. In an alternative embodiment, the virus may be an arenavirus, phlebovirus, hantavirus, flavivirus, enterovirus, alphavirus, influenza virus, SFTS virus, Ebola virus, or Lassa virus.

[0038] Alternatively, a method for treating a subject having an early-stage infection by a microbe comprising administering to the subject a combination of an antimicrobial agent and a cathepsin inhibitor, wherein the early-stage infection is determined by a lateral flow assay is provided. The microbe causing the early-stage infection may be a virus, such as a coronavirus or, specifically, the SARS-CoV-2 virus. In other embodiments, the virus may be an arenavirus, phlebovirus, hantavirus, flavivirus, enterovirus, alphavirus, influenza virus, SFTS virus, Ebola virus, or Lassa virus.

[0039] In some embodiments, the antiviral agent is a purine nucleic acid analog or, more specifically, an agent that inhibits RNA-dependent RNA polymerase (RDRP). In a specific embodiment, the antiviral agent may include favipiravir, favipiravir-RTP, remdesivir, and molnupiravir. In a preferred embodiment, the antiviral agent is favipiravir. In a further embodiment, the cathepsin inhibitor may be a cathepsin K inhibitor. The cathepsin K inhibitor may be balicatib or relacatib. In a specific preferred embodiment, the virus may be the SARS- CoV-2 virus, the antiviral agent may be favipiravir, and the cathepsin inhibitor may be balicatib. [0040] In embodiments where the microbial infection is a bacterial infection, the antimicrobial agent would be an antibacterial agent (e.g., an antibiotic). In embodiments where the microbial infection is a parasitic infection, the antimicrobial agent would be an antiparasitic agent. In embodiments where the microbial infection is a fungal infection, the antimicrobial agent would be an antifungal agent. In embodiments where the microbial infection is a fungal infection, the antimicrobial agent would be an antifungal agent.

[0041] The amount of favipiravir for treating the SARS-CoV-2 infection is described above. In some embodiments, the method may comprise administration two doses of favipiravir per day. In some embodiments, the two doses of favipiravir on the first day (e.g., the loading doses) may be greater than the doses of favipiravir on subsequent days. In a particular embodiment, the first- day doses of favipiravir may each be between about 1600 mg and about 1800 mg and the doses of favipiravir on subsequent days may each be between about 400 mg and about 800 mg.

[0042] In a further embodiment, the method comprises the step of administering a cathepsin inhibitor. In a particular embodiment, the cathepsin inhibitor may be balicatib or relacatib. In a preferred embodiment, the cathepsin inhibitor is balicatib. The amount of balicatib or relacatib for treating SARS-CoV-2 is described above. In a particular embodiment, the balicatib or relacatib may be administered at a dose of between about 10 and about 50 mg. In a specific embodiment, the first day doses of favipiravir may each be between about 1600 mg and about 1800 mg, the subsequent doses of favipiravir may each be between about 400 mg and about 800 mg, and the dose of balicatib or relacatib throughout the course of treatment is between about 10 and about 50 mg.

[0043] The antimicrobial agent (such as an antiviral agent) and the cathepsin inhibitor may be formulated in a single pharmaceutical composition. The antiviral agent may comprise at least 50% by weight of the total weight of the pharmaceutical composition. In such an embodiment, the cathepsin inhibitor may comprise less than 50% by weight of the total weight of the composition. Alternatively, the cathepsin inhibitor may comprise at least 50% by weight of the total weight of the pharmaceutical composition. In such an embodiment, the antiviral agent may comprise less than 50% by weight of the total weight of the pharmaceutical composition.

[0044] As mentioned above, the method described herein may be useful for treating a coronavirus infection. More specifically the virus may be the SARS-CoV-2 virus. In such embodiments, the method may comprise administering to the subject an antiviral agent and a cathepsin inhibitor. In a preferred embodiment, the antiviral agent may be favipiravir and the cathepsin inhibitor may be balicatib or relacatib.

[0045] The amount of favipiravir for treating the SAR-CoV-2 infection is described above. In some embodiments, the method may comprise administration two or more doses of favipiravir per day. The two or more doses of favipiravir on the first day (e.g., the loading doses) may be greater than the doses of favipiravir on subsequent days. In a particular embodiment, the first- day doses of favipiravir may each be between about 1600 mg and about 1800 mg and the doses of favipiravir on subsequent days are each between about 400 mg and about 800 mg. The amount of balicatib or relacatib for treating SARS-CoV-2 is described above. In a particular embodiment, the balicatib or relacatib may be administered at a dose of between about 10 and about 50 mg. Further, the first day doses of favipiravir may each be between about 1600 mg and about 1800 mg, the subsequent doses of favipiravir may each be between about 400 mg and about 800 mg, and the dose of balicatib or relacatib throughout the course of treatment may be between about 10 and about 50 mg.

[0046] In a particular embodiment, first doses of favipiravir are administered on Day 0 and subsequent favipiravir doses may be administered daily on multiple subsequent days and balicatib or relacatib is administered on Day 1 and on multiple subsequent days. For example, a loading dose of favipiravir may be administered on Day 0, and on subsequent doses may be administered on Days 2-30, Days, 2-25, Days 2-20, Days 2-15, Days 2-10, or Days 2-5. Additionally, the balicatib or relacatib may be administered on Days 1-60, Days 1-55, Days 1- 50, Days 1-45, Days 1-40, Days 1-35, Days 1-30, Days 1-25, Days 1-20, Days 1-20, Days 1-15, Days 1-10, and Days 1-5. In a particular schedule, the favipiravir may be administered on Days 0 (as a loading dose) and on Days 2-5 and balicatib or relacatib may be administered on Days 1- 10. As described in the above schedule, the favipiravir and balicatib or relacatib may be administered on the same day. For each day administered, the favipiravir and/or balicatib or relacatib may be administered QD, BID, TID, QID, or more. When the favipiravir and balicatib or relacatib are administered on the same day, both agents may be administered simultaneously (e.g., as part of a singular formulation), concurrently (where one agent is administered immediately after the other), or with a period of time between administration of each dose. [0047] The terminology used herein is for the purpose of describing particular example embodiments only and is not intended to be limiting. As used herein, the singular forms “a,” “an,” and “the” may be intended to include the plural forms as well, unless the context clearly indicates otherwise. The terms “comprises,” “comprising,” “including,” and “having,” are inclusive and therefore specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the particular order discussed or illustrated, unless specifically identified as an order of performance. It is also to be understood that additional or alternative steps may be employed.

[0048] The term “about” when applied to values indicates that the calculation or the measurement allows some slight imprecision in the value (with some approach to exactness in the value; approximately or reasonably close to the value; nearly). If, for some reason, the imprecision provided by “about” is not otherwise understood in the art with this ordinary meaning, then “about” as used herein indicates at least variations that may arise from ordinary methods of measuring or using such parameters. For example, the terms “generally,” “about,” and “substantially,” may be used herein to mean within manufacturing tolerances. Or for example, the term “about” as used herein when modifying a quantity of an ingredient or reactant of the invention or employed refers to variation in the numerical quantity that can happen through typical measuring and handling procedures used, for example, when making concentrates or solutions in the real world through inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make the compositions or carry out the methods; and the like. The term “about” also encompasses amounts that differ due to different equilibrium conditions for a composition resulting from a particular initial mixture. Whether or not modified by the term “about,” the claims include equivalents to the quantities.

[0049] Although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and/or sections, these elements, components, regions, layers and/or sections should not be limited by these terms. These terms may be only used to distinguish one element, component, region, layer or section from another region, layer or section. Terms such as “first,” “second,” and other numerical terms when used herein do not imply a sequence or order unless clearly indicated by the context. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the example embodiments.

[0050] With that said, the foregoing description of the embodiments has been provided for purposes of illustration and description. It is not intended to be exhaustive or to limit the disclosure. Individual elements or features of a particular embodiment are generally not limited to that particular embodiment, but, where applicable, are interchangeable and can be used in a selected embodiment, even if not specifically shown or described. The same may also be varied in many ways. Such variations are not to be regarded as a departure from the disclosure, and all such modifications are intended to be included within the scope of the disclosure.