WO2021183259A1

WO2021183259A1 - Famotidine and famotidine analogs for corona virus treatment

Info

Publication number: WO2021183259A1
Application number: PCT/US2021/018097
Authority: WO
Inventors: James Talton
Original assignee: Nanopharmaceutics, Inc.
Priority date: 2020-03-12
Filing date: 2021-02-15
Publication date: 2021-09-16

Abstract

In silico screening of currently approved drugs against coronavirus SARS-CoV-2, PLpro (papain-like protease) resulted in the identification of famotidine and related analogs as potential antiviral candidates. PLpro (papain-like protease), a coronaviral protease, is essential for coronaviral replication. Famotidine, a histamine H2 antagonist, and a series of analogs repeatedly docked in the Cysl 12/His273/Asp287 catalytic triad pocket scored among the highest of the FDA-approved and over-the-counter compounds tested. Currently available as oral and IV products, famotidine appears in preliminary in silico screens to be useful to block PLpro activity and may be a potential treatment in patients who have contracted COVID-19 disease (caused by 2019-nCoV / SARS-CoV-2 infection). Famotidine has a very attractive profile with proven safety, drug interaction, and therapeutic window profiles.

Description

FAMOTIDINE AND FAMOTIDINE ANALOGS FOR CORONAVIRUS TREATMENT

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 62/988,539, filed on March 12, 2020, which is incorporated herein by reference in its entirety.

BACKGROUND

[0001] In silico screening of currently approved drugs against coronavirus SARS-CoV-2, PLpro (papain-like protease) resulted in the identification of Famotidine and related analogs as potential antiviral candidates, PLpro (papain-like protease), a coronaviral protease, is essential for coronaviral replication. Famotidine, a histamine H2 antagonist, and a series of analogs repeatedly docked in the Cysl 12/His273/Asp287 catalytic triad pocket scored among the highest of the FDA-approved and over-the-counter compounds tested. Currently available as oral and IV products, Famotidine appears in preliminary in silico screens to be useful to block PLpro activity and may be a potential treatment in patients who have contracted COVID- 19 disease (caused by 2019-nCoV / SARS-CoV-2 infection). Famotidine has a very attractive profile with proven safety, drug interaction, and therapeutic window profile.

[0002] Histamine and specific agonists of different histamine receptors have been shown to promote viral lytic replication (Chen et.al. “Identification of new antiviral agents against Kaposi's sarcoma-associated herpesvirus (KSHV) by high-throughput drug screening reveals the role of histamine-related signaling in promoting viral lytic reactivation.” PLoS Pathog. 2019 Dec 2;15(12):el008156. doi: 10.1371/j oumal.ppat.1008156. eColiection 2019 Dec. PMID:

31790497) “Mechanistic studies indicated that downstream MAPK and PBK/Akt signaling pathways were required for histamine/receptors mediated promotion of KSHV lytic replication. Direct knockdown of HxRs in iSLK.219 ceils effectively blocked viral lytic gene expression during induction. Using samples from a cohort of HIV+ patients, we found that the KSHV+ group has much higher levels of histamine in their plasma and saliva than the KSHV- group.” Famotidine demonstrated a 300 mM IC50 in vitro against KSHV.

[0003] In “Repurposing Potential of 1st Generation I H 1 -spec ifi Antihistamines as Anti-filovirus Therapeutics” (Schafer et.al, Antiviral Res. 2018 Sep;157:47-56. doi: 10.1016/j. antiviral.2018.07.003. Epub 2018 Jul 4. PMID: 29981374), an “FDA-approved drug library was screened and identified numerous G protein-coupled receptor (GPCR) antagonists including antihistamines possessing anti-filovirus properties. In this report Schafer et.al identified common over the counter antihistamines, such as diphenhydramine (Benadryl) and chlorcyclizine (Ahist) as potential candidates for repurposing as anti-filovirus agents. It was demonstrated that this potential is wide-spread through the 1st generation of HI -specific antihistamines but is not present in newer drugs or drugs targeting H2, H3 and H4 receptors for filovirus. Filovirus entry inhibition is not dependent on the classical antagonism of cell surface histamine or muscarinic acetylcholine receptors but occurs in the endosome, like the cathepsin inhibitor CA-074. Finally, using extensive docking studies they showed the potential for these drugs to bind directly to the EBOV-GP at the same site as toremifene.”

[0004] Famotidine has been shown to have a direct effect in Angeotensin-II levels, linked to coronavirus entry into pulmonary cells. Halici, et.al. (“Inhibiting renin angiotensin system in rate limiting step by aliskiren as a new approach for preventing indomethacin induced gastric ulcers” Chem Biol Interact. 2016 Oct 25;258:266-75. doi: 10.1016/j. cbi.2016.09.011. Epub 2016 Sep 16, PMID: 27645307) showed that “famotidine decreased ulcer formation and oxidative stress significantly. Famotidine or indomethacin administration also increased tissue renin concentrations. However, this increase was not significantly different from only the indomethacin group. When we checked Ang II as endproduct of RAAS, they saw that famotidine decreased tissue Ang II concentration when compared to indomethacin, but this decreasing effect was not as strong as aliskiren's. Famotidine is known as histamine H2 receptor antagonist and used as standard antiulcer agent with antioxidative properties. Decrease in Ang II, but not renin concentrations, can be related to famotidine's antioxidative effect that blocked endproduct (Ang II) occurrence. As another possible mechanism of action, famotidine might decrease tissue Ang II by blocking H2 receptors. Namely histamine, the main stimulator of H2 receptors, has been reported to activate the RAAS. In our study, blocking effects of histamine by H2 receptor antagonist could the result of in inactivation of RAAS at some point of the process. There is no known study that has investigated the relation between stomach H2 receptors and RAAS system. [0005] Halici, et.al. (2016) also stated “In accordance with our results, previous studies demonstrated that indomethacin-induced acute gastric damage resulted in increased local production of TNFa and IL-lb. In our study, both aliskiren and famotidine administration significantly decreased the mRNA expression of inflammatory cytokines. During ulcer, occurrence in addition to increased aggressive factors such as oxidative stress, inflammation etc. decreased protective factors such as PGE2 takes role. In this study, we evaluated the effects of aliskiren on local COX enzymes and their end-product PGE2 levels in stomach tissues. Our results demonstrated that indomethacin administration decreased PGE2 levels significantly, while aliskiren and famotidine increased PGE2. Indomethacin is known as a cyclooxygenase enzyme inhibitor that binds to the active site of COX enzymes and inactivates them. In our study, indomethacin, surprisingly, increased the mRNA expression of both COX enzymes. This increase in COX mRNA expression can be due to the negative-feedback response against inhibited COX activity, and thus, decreased end-product: PGE2. Prostaglandin E2 is a well established mediator in gastric mucosal defense and repair.”

[0006] Further, Halici, et.al. (2016) also stated “In our study, indomethacin-induced PGE2 depletion was improved by both famotidine and aliskiren, which acted as gastro-protective agents. Here the increase in PGE2 levels in both famotidine and aliskiren treatment can be a parallel response to antiulcer effect. Both aliskiren and famotidine ameliorated protective factors such as PGE2 and antioxidant defense mechanisms against aggressive factors, and regulated balance of stomach tissue. On the other hand, previous studies have suggested that ANG II increases PGE2 synthesis and release through phospholipase A2 stimulation, balancing its vasoconstrictor effects. The role of Ang II receptor types on PGE2 formation and release is controversial and may be mediated through AT2 or ATI receptor stimulation. In addition, Ang II stimulates COX-2, leading not only to inflammation, but also to increased PGE2 synthesis; this effect is mediated by ATI receptor activation. In previous studies Ang II is shown to increase the synthesis of arachidonic acid derivatives such as prostaglandins in vascular smooth-muscle cells, and leukotrienes, via activation of the COX and lipoxygenase pathways, respectively.”

[0007] Histamine and specific agonists of different histamine receptors have been shown to exert potent modulatory impacts on the cells of innate [including neutrophils, monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells and NKT cells] and adaptive immunity (such as Thl-, Th2-, Thl7-, regulatory T-, CD8+ cytotoxic T cells, and B cells) through binding to histamine receptor 2 (H2R). Cimetidine, as an H2R antagonist, reverses the histamine-mediated immunosuppression, as it has powerful stimulatory effects on the effector functions of neutrophils, monocytes, macrophages, DCs, NK cells, NKT cells, Thl-, Th2-,

B Thl7-, and CD8+ cytotoxic T cells. However, cimetidine reduces the regulatory/suppressor T cell mediated immunosuppression. Experimentally, cimetidine potentiates some immunologic activities in vitro and in vivo. The therapeutic potentials of cimetidine as an immunomodulatory agent were investigated in a number of human diseases (such as cancers, viral warts, allergic disorders, bum, and bone resorption) and vaccination in “Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases.” (Jafarzadeh et.ak, Int Immunopharmacol. 2019 May;70: 156-166. doi: 10.1016/j.intimp.2019.02.026. Epub 2019 Feb 22. PMID: 30802678)

[0008] Finally, in “Histamine receptors and COVID-19”, Inflamm Res. 2020 Nov 18: 1-9, PMID: 33206207, Ennis and Tiligada stated “Histamine is a main mediator that is being released by immune system and other cells as a result of vims invasions or activation. Histamine initiates abnormal immune response leading to cytokine storm and multi-organs failure. Thus, the use of antihistaminic medications could result in a significant immune modulation which may help in the treatment of cytokine storm of COVID-19. Future studies could compare H2R antagonists with those of steroid therapy in addition to the effect of combination therapy in relation to standard therapy.”

[0009] In conclusion, the mechanism of action (MO A) of famotidine and related analogs in COVID-19 patients may or may not be from direct antiviral activity through PLpro protease inhibition but may be through its antihistamine, immunomodulatory, or another mechanism. Further in vivo or clinical studies are required to ascertain the MOA for the efficacy observed in COVID-19 patients.,

SUMMARY OF THE INVENTION

[0010] The present invention relates to famotidine and related analogs for oral or intravenous delivery to a patient wherein the compounds are capable of blocking the papain-like protease of coronavirus. The present invention describes compounds including famotidine, 3-[(2- guanidinothiazol-4-yl)methylsulfanyl]-N'-sulfamoyl-propanamidine or N'-(Aminosulfonyl)-3- ([2-(diaminomethyleneamino)-4-thiazolyl]methylthio)propanamidine,

FAMOl 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N- sulfamoylpropanamide, FAM02 3-[2-[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]ethylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM03 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]-N'- sulfamoylpropanimidamide,

FAM04 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM05 3-[[2-[(N'-methylcarbamimidoyl)amino]-l,3-thiazol-4-yl]methylsulfanyl]-

N'-sulfamoylpropanimidamide,

FAM06 4-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylbutanimidamide,

FAM07 2-[4-[2-(5-Amino-l,l-dioxo-4H-l,2,4,6-thiatriazin-3- yl)ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

FAM08 2-[2-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]ethyl]-l-sulfamoylguanidine,

FAM09 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]-N'- sulfamoylpropanimidamide,

FAMOIO 3-[[2-[(E)-Hydrazinylmethylideneamino]-l,3-thiazol-4- yl]methylsulfanyl]-N'-sulfamoylpropanimidamide,

FAM012 3-[[2-[(E)-hydrazinylmethylideneamino]-l,3-thiazol-4-yl]methylsulfanyl]-

N'-sulfamoylpropanimidamide,

FAM013 Famotidine cyanoamidine,

FAM014 N'-cyano-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propanimidamide,

FAM015 3-((2-(Diaminomethyleneamino)thiazol-4- yl)methylthio)propanimidamide,

FAM018 (Z)-[l-amino-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propylidene]urea,

FAM019 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM021 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide, FAM022 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-2- sulfamoylpropanimidamide,

FAM024 l-[4-(2-cyanoethylsulfanylmethyl)-l,3-thiazol-2-yl]-l- sulfamoylguanidine,

FAM025 2-[4-[[(3E)-3-(Hydrazinesulfonylimino)propyl]sulfanylmethyl]-l,3- thiazol-2-yl]guanidine,

FAM026 N'-Cyano-N-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propanimidamide,

FAM028 (E)-[l-Amino-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propylidene]urea,

FAMO30 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(trifluoromethylsulfonyl)propanimidamide,

FAM031 4-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylbutanimidamide,

FAM032 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N- sulfamoyl-N-trimethylsilylpropanimidamide,

FAM033 2-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propanimidamide,

FAM034 3-[({2-[(diaminomethylidene)amino]-l,3-thiazol-4-yl}methyl)sulfanyl]-

N'-sulfamoylpropanimidamide,

FAM036 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM037 Famotidine hydrochloride,

FAM042 3-[[2-[bis(dideuterioamino)methylideneamino]-5-deuterio-l,3-thiazol-4- yl]methylsulfanyl]-N,N-dideuterio-N'-(dideuteriosulfamoyl)propanimidamide,

FAM047 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM048 2-[4-[[3-amino-3-(sulfamoylamino)propyl]sulfanylmethyl]-l,3-thiazol-2- yljguanidine,

FAM049 [[l-Amino-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propylidene]amino]sulfonylazanide, F AM050 2- [4- [ [3 -(Hy drazinesulfonylimino)propylthio]methyl] -2- thiazolyljguanidine

FAM052 [l-Amino-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propylidene]urea,

FAM054 N-Methanesulfonyl-3-[(2-guanidinothiazol-4- yl)methylthio]propionamidine,

FAM055 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- methylsulfonylpropanimidamide,

FAM056 3-[(2-Guanidinothiazol-4-yl)methylthio]propionamidoxime,

FAM057 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- hydroxypropanimidamide,

FAM058 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanylsulfamoyl]propanimidamide,

FAMO60 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- methylpropanimidamide,

FAM062 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM064 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylprop-2-enimidamide,

FAM067 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-3- methylsulfonylpropanimidamide,

FAM068 N'-[4-[[(3E)-3-(Hydrazinesulfonylimino)propyl]sulfanylmethyl]-l,3- thi azol -2-y 1 ] ethanimi dami de,

FAMO70 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM072 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(hydroxymethyl)-N-sulfamoylpropanimidamide,

FAM073 2-[2-[[2-(Diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]ethyl]-l-(methylsulfamoyl)guanidine,

FAM074 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(trifluoromethylsulfonyl)propanimidamide, FAM075 N'-[4-[3-(Hydrazinesulfonylimino)propylsulfanylmethyl]-l,3-thiazol-2- yljethanimidamide,

FAM076 2-[4-[[(E)-3-Amino-3-(sulfamoylamino)prop-2-enyl]sulfanylmethyl]-l,3- thiazol-2-yl]guanidine,

FAM077 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-3- sulfamoylpropanimidamide,

FAM079 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(hydroxymethyl)-N-sulfamoylpropanimidamide,

FAM081 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM082 Methyl N'-[2-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]ethyl]-N-sulfamoylcarbamimidothioate,

FAM083 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- methylsulfonylpropanimidamide,

FAM084 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(dimethylsulfamoyl)propanimidamide,

FAM085 3-[[2-(diaminomethybdeneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N,N'- disulfamoylpropanimidamide,

FAM086 2-[4-[2-(l, l-Dioxo-3,6-dihy dro-2H- 1,2,4, 6-thiatriazin-5- yl)ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

FAM087 5-[2-[[2-(Diaminomethyleneamino)-4-thiazolylmethyl]thio]ethyl]-3,4- dihydro-2H- 1 ,2,4,6-thiatriazine 1 , 1 -dioxide,

FAM089 [2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate,

FAM091 N'-Aminoperoxysulfanyl-2-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]ethanimidamide,

FAM092 [2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate,

FAM094 [2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- methylsulfonylcarbamimidothioate, FAM095 3-[[2-(Dimethylamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM096 2,2,3,3-tetradeuterio-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]-N'-sulfamoylpropanimidamide,

FAM097 2-[4-[2-(3-Methyl-l, 1-di oxo-3, 6-dihydro-2H-l, 2,4, 6-thiatriazin-5- yl)ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

FAM098 3-[[[[2-[(diaminomethylene) amino]-4-thiazolyl]methyl]thio]thio]-n2- sulfamyl propionamidine,

FAM099 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methyldisulfanyl]-N'- sulfamoylpropanimidamide,

FAMOIOO 3-[[2-[(E)-Hydrazinylmethylideneamino]-l,3-thiazol-4- yl]methylsulfanyl]-N'-sulfamoylpropanimidamide,

FAMOIOI 4-[[(3Z)-3-amino-3-(hydroxysulfonimidoyl)iminopropyl]sulfanylmethyl]- 2-(diaminomethylideneamino)-l,3-thiazole,

FAMO102 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

F AMO 104 2-[4-[2-[(4-amino- 1 , 1 -dioxo- 1 ,2, 5-thiadiazol-3 - ylidene)amino]ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

FAMO105 3-[(S)-[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]-

N'-sulfamoylpropanimidamide,

F AMO 106 [1 -amino-3 -[[2-[(E)- 1 -aminoethylideneamino]- 1 ,3 -thiazol-4- yl]methylsulfanyl]propylidene]urea,

FAMO107 [2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate,

FAMO109 3-[[2-[(E)-l-Aminoethylideneamino]-l,3-thiazol-4-yl]methylsulfanyl]-N- hydrazinylidene-N'-sulfamoylpropanimidamide,

FAMOl 10 N'-Aminoperoxysulfanyl-2-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]ethanimidamide,

FAMOl 11 [2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate, FAM0112 [2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- methylsulfonylcarbamimidothioate,

FAMOl 13 3-[[2-(dimethylamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAMOl 14 2,2,3,3-Tetradeuterio-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]-N'-sulfamoylpropanimidamide,

FAMOl 15 2-[4-[2-(3-Methyl-l,l-dioxo-3,6-dihydro-2H-l,2,4,6-thiatriazin-5- yl)ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

FAMOl 16 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyldisulfanyl]-N'- sulfamoylpropanimidamide,

FAMOl 17 3-[[[[2-[(diaminomethylene) amino]-4-thiazolyl]methyl]thio]thio]-n2- sulfamyl propionamidine,

FAMOl 18 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methyldisulfanyl]-N'- sulfamoylpropanimidamide,

FAMOl 19 3-[[2-[(E)-Hydrazinylmethylideneamino]-l,3-thiazol-4- yl]methylsulfanyl]-N'-sulfamoylpropanimidamide,

FAMO120 3-[((2-((aminoiminomethyl)amino)-4-thiazolyl)methyl)thio]-N'- (aminosulfonyl)propaneimidamide,

FAM0121 4-[[(3Z)-3-amino-3-(hydroxysulfonimidoyl)iminopropyl]sulfanylmethyl]- 2-(diaminomethylideneamino)-l,3-thiazole,

FAM0122 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

F AMO 123 2-[4-[2-[(4- Amino- 1 , 1 -dioxo- 1 ,2, 5-thiadiazol-3 - ylidene)amino]ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

F AMO 124 2-[4-[ 1 -[(4-amino- 1 , 1 -dioxo- 1 ,2, 5-thiadiazol-3 -ylidene)amino]propan-2- ylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

FAM0126 3-[(S)-[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]-N'- sulfamoylpropanimidamide,

F AMO 128 [1 -amino-3 -[[2-[(E)- 1 -aminoethylideneamino]- 1 ,3 -thiazol-4- yl]methylsulfanyl]propylidene]urea, FAM0129 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N- sulfamoylpropanamide,

FAMO130 3-[2-[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]ethylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM0131 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]-N'- sulfamoylpropanimidamide,

FAM0132 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- hydroxypropanimidamide.

DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 shows the structures of the compounds described immediately above, including famotidine, 3-[(2-guanidinothiazol-4-yl)methylsulfanyl]-N'-sulfamoyl-propanamidine or N'- (Aminosulfonyl)-3-([2-(diaminomethyleneamino)-4-thiazolyl]methylthio)propanamidine (FAMOl), and analogs (FAM02 to FAM0132) thereof.

[0012] Figure 2 shows famotidine docked to the PLpro Cysl 12/His273/Asp287 catalytic triad pocket and bonding interactions.

DETAILED DESCRIPTION

[0012] Disclosed herein are famotidine and related analogs that are inhibitors of coronavirus SARS-CoV-2, PLpro (papain-like protease). The compounds include famotidine and related analogs that may be used as potential antiviral candidates. PLpro (papain-like protease), a coronaviral protease, is essential for coronaviral replication. Famotidine, a histamine H2 antagonist, and a series of analogs repeatedly docked in the Cysl 12/His273/Asp287 catalytic triad pocket scored among the highest of the FDA-approved and over-the-counter compounds tested.

[0013] Also disclosed herein are famotidine and related analogs that include the compositions disclosed herein and methods of treatment utilizing such compositions.

[0014] Also disclosed herein are methods of treating coronavirus, comprising, providing a pharmaceutical formulation comprising an effective amount of famotidine and related analogs as described above, and administering said pharmaceutical formulation to a patient in need thereof. [0015] As examples of compounds that may be used in accordance with the present disclosure, non-limiting mention is including famotidine, 3-[(2-guanidinothiazol-4-yl)methylsulfanyl]-N'- sulfamoyl-propanamidine or N'-(Aminosulfonyl)-3-([2-(diaminomethyleneamino)-4- thiazolyl]methylthio)propanamidine,

FAMOl 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N- sulfamoylpropanamide,

FAM02 3-[2-[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]ethylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM05 3-[[2-[(N'-methylcarbamimidoyl)amino]-l,3-thiazol-4-yl]methylsulfanyl]-

N'-sulfamoylpropanimidamide,

FAM012 3-[[2-[(E)-hydrazinylmethylideneamino]-l,3-thiazol-4-yl]methylsulfanyl]-

N'-sulfamoylpropanimidamide,

FAMOl 3 Famotidine cyanoamidine,

FAMOl 5 3-((2-(Diaminomethyleneamino)thiazol-4- yl)methylthio)propanimidamide, FAM018 (Z)-[l-amino-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propylidene]urea,

FAM021 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM022 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-2- sulfamoylpropanimidamide,

FAMO30 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(trifluoromethylsulfonyl)propanimidamide,

FAM034 3-[({2-[(diaminomethylidene)amino]-l,3-thiazol-4-yl}methyl)sulfanyl]-

N'-sulfamoylpropanimidamide,

FAM037 Famotidine hydrochloride,

I B FAM047 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM049 [[l-Amino-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propylidene]amino]sulfonylazanide,

F AM050 2- [4- [ [3 -(Hy drazinesulfonylimino)propylthio]methyl] -2- thiazolyljguanidine

FAM054 N-Methanesulfonyl-3-[(2-guanidinothiazol-4- y l)methy lthi o] propi onami dine,

FAM056 3-[(2-Guanidinothiazol-4-yl)methylthio]propionamidoxime,

FAMO70 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide, FAM072 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(hydroxymethyl)-N-sulfamoylpropanimidamide,

FAM074 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(trifluoromethylsulfonyl)propanimidamide,

FAM075 N'-[4-[3-(Hydrazinesulfonylimino)propylsulfanylmethyl]-l,3-thiazol-2- y 1 ] ethanimi dami de,

FAM079 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(hydroxymethyl)-N-sulfamoylpropanimidamide,

FAM084 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(dimethylsulfamoyl)propanimidamide,

FAM085 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N,N'- disulfamoylpropanimidamide,

FAM089 [2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate, FAM091 N'-Aminoperoxysulfanyl-2-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]ethanimidamide,

FAM094 [2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- methylsulfonylcarbamimidothioate,

FAM095 3-[[2-(Dimethylamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAMOIOI 4-[[(3Z)-3-amino-3-(hydroxysulfonimidoyl)iminopropyl]sulfanylmethyl]-

2-(diaminomethylideneamino)-l,3-thiazole,

FAMO105 3-[(S)-[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]-

N'-sulfamoylpropanimidamide,

FAMO107 [2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate, FAMO109 3-[[2-[(E)-l-Aminoethylideneamino]-l,3-thiazol-4-yl]methylsulfanyl]-N- hydrazinylidene-N'-sulfamoylpropanimidamide,

FAMOl 11 [2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate,

FAMOl 12 [2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- methylsulfonylcarbamimidothioate,

FAMOl 15 2-[4-[2-(3-Methyl-l, 1-di oxo-3, 6-dihydro-2H-l, 2,4, 6-thiatriazin-5- yl)ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

F AMO 123 2-[4-[2-[(4- Amino- 1 , 1 -dioxo- 1 ,2, 5-thiadiazol-3 - ylidene)amino]ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine, F AMO 124 2-[4-[ 1 -[(4-amino- 1 , 1 -dioxo- 1 ,2, 5-thiadiazol-3 -ylidene)amino]propan-2- ylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

F AMO 128 [1 -amino-3 -[[2-[(E)- 1 -aminoethylideneamino]- 1 ,3 -thiazol-4- yl]methylsulfanyl]propylidene]urea,

FAM0129 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N- sulfamoylpropanamide,

[0016] Another aspect of the present disclosure relates to pharmaceutical formulations comprising famotidine and related analogs described herein.

[0017] In some embodiments, the pharmaceutical formulations further comprise at least one excipient, such as a water-soluble polymer, a surfactant, and/or another enhancer such as a pharmaceutically acceptable excipient. Non-limiting examples of pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences by E. W. Martin, and include cellulose, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. In some embodiments, the pharmaceutical formulations also contain pH buffering reagents, and wetting or emulsifying agents.

[0018] The pharmaceutical formulations of the present disclosure can be in the any form suitable for administration to a patient, such as in the form of an oral tablet or capsule, or an intravenous solution or suspension. The pharmaceutical formulations may also contain various additional ingredients, such as suspending, stabilizing and/or dispersing agents.

[0019] In some embodiments, the pharmaceutical formulations incorporating famotidine and related analogs described herein, such as in the form of an oral tablet or capsule, provide concentrations of famotidine and related analogs with inactive ingredients. For example, the concentration of famotidine and related analogs may be, e.g., at least 10%, 15%, 20%, 25%,

30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 93%, 95%, 96%, 97%, 98%, 99%, or 100% or diluted by, e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, or 1000 fold. In some embodiments, the pharmaceutical formulations incorporating famotidine and related analogs described herein, such as in the form of an oral tablet or capsule, contain dosages less than 1 milligram to over 100 milligrams.

[0020] In some embodiments, the pharmaceutical formulations incorporating famotidine and related analogs are in the form of an immediate-release formulation or a controlled-release formulation.

[0021] In some embodiments, the pharmaceutical formulations incorporating famotidine and related analogs described herein are associated with improved patient compliance, relative to another pharmaceutical formulation comprising the same compound (which may be in another dosage form, e.g., a more invasive dosage form such as an injectable product).

[0022] As used herein, the terms "treat," treatment," and "treating" refer to (1) a reduction in severity or duration of a disease or condition, (2) the amelioration of one or more symptoms associated with a disease or condition without necessarily curing the disease or condition, or (3) the prevention of a disease or condition. Suitable subjects include, e.g., humans and other mammals, such as, e.g., mice, rats, dogs, and non-human primates.

EXAMPLES

[0023] The following examples are intended to be purely exemplary of the present invention. [0024] EXAMPLE 1 - In silico screening of PLpro protease:

[0025] SARS-CoV-2 has caused millions of infections and more than four hundred thousand deaths. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. The proteins encoded by SARS- CoV-2 genes have demonstrated similarity with proteins from other coronaviruses by homology modeling. PLpro, a viral protease, is responsible for the cleavages of N-terminus of the replicase poly-protein to release Nspl, Nsp2 and Nsp3, which is essential for virus replication. By performing target-based virtual ligand screening, the Cysl 12/His273/Asp287 catalytic triad pocket of several PLpro structures were screened against compound libraries including ZINC drug database and other publicly available databases. In addition, a database of thousands of commonly used drugs including those currently on the market and undergoing clinical trials was constructed. Possible targets of these compounds, including the Cysl 12/His273/Asp287 catalytic triad pocket, and potential drugs acting on this target were predicted. These studies identified lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.

[0026] The protein structures 3E9S (2008) - papain-like protease (PIPro) of human SARS coronavirus, 3MJ5 (2010) - SARS-Coronavirus Papain-Like Protease, and 4MOW (2013) - SARS-CoV PIPrp Cl 12S mutant were used having resolved crystal structures for screening. Initial in silico screening of compound libraries were performed using (1) an FDA-approved in silico compound list (866 compounds), (2) 5,000 and 10,000 compound diversity sets and (3) expanded FDA-approved and OTC compound list (2,600 compounds). The inventor retrospectively evaluated the ability of the model to properly rank high-affinity compounds by in silico molecular modelling of specific protein structure-drug interactions, and then performed rigorous studies to assess, refine and verify the predictive accuracy of the docking model, followed by in silico docking of compounds. For docking the compound libraries into the protein crystal structure, Molecular Forecaster’s FITTED software was used, and the compounds ranked by score. The enrichment with each crystal structure (and flexible docking) was tested using different settings. Additionally, UCSF Chimera, a suite of advanced protein structure database and analysis tools, was also used to quickly compare, overlay and analyze important binding site properties and ligand interactions. Intensive computing of virtual screens was carried out using an Azure multi-CPU Virtual Machine (VM). FITTED is run on VM with 16-64 CPUs. This list was then further screened by reviewing FDA package inserts, known bioavailability, pharmacokinetic and toxicity profiles, plasma protein binding, known on-target activities and clinical indications. This final filter yielded a final list of lead compound candidates for inhibition of SARS-CoV-2 PLpro. All results of calculated docking scores were listed in the excel and significant scores (score<-20) were identified. Of the libraries screened, famotidine and the listed famotidine analogs were among the highest ranked compounds. The docked structure of famotidine is shown in Figure 2 and the interactions shown in Tables 1 and 2 below. Table 1: Hydrophobic Interactions

Index Residue AA Distance Ligand Atom Protein Atom 1 267 A TYR 3.78 4950 4134

Table 2: Hydrogen Bonds i Inde Residu AA Distanc Distance Donor Protein Side- Donor Acceptor

: x e e H-A D-A Angle donor? chain Atom Atom

1 160A LYS 3.17 4.09 151.30 X X 2506 [N3+] 4942 [02]

2 165A LEU 1.99 2.99 165.32 H 4947 [N3] 2575 [02]

3 166A GLY 2.95 3.87 151.01 X It 4943 [Npl] 2594 [02]

4 167 A ASP 3.21 4.03 147.69 X V 2605 [03] 4945 [N2]

5 167 A ASP 2.57 2.99 104.57 X 2598 [Nam] 4942 [02]

6 169A AR 2.86 3.71 142.37 ^' X 2626 [Nam] 4948 [Ng+]

G

7 169A AR 2.29 3.25 156.72 X X 2633 [Ng+] 4946 [Ng+]

G

8 249A ALA 2.88 3.68 136.51 X X 3856 [Nam] 4949 [Ng+]

9 272 A GLN 3.30 3.94 123.01 X X^' 4202 [Nam] 4945 [N2]

10 276 A TYR 3.08 3.88 135.39 If X 4948 [Ng+] 4265 [03]

11 304A THR 2.17 3.02 137.46 X X 4949 [Ng+] 4710 [02]

[0027] EXAMPLE 2 - Famotidine use and quantitative symptom tracking for COVID-19 in non- hospitalized patients:

[0028] A case series (Janowitz T, Gablenz E, Pattinson D, Wang TC, Conigliaro J, Tracey K, Tuveson D. Gut. 2020 Sep;69(9): 1592-1597. doi: 10.1136/gutjnl-2020-321852. Epub 2020 Jun 4). Treatment options for non-hospitalized patients with coronavirus disease 2019 (COVID-19) to reduce morbidity, mortality and spread of the disease are an urgent global need. The over-the- counter histamine-2 receptor antagonist famotidine is a putative therapy for COVID-19. We quantitively assessed longitudinal changes in patient reported outcome measures in non- hospitalized patients with COVID-19 who self-administered high-dose famotidine orally.

[0028] Patients were enrolled consecutively after signing written informed consents. Data on demographics, COVID-19 diagnosis, famotidine use, drug-related side effects, temperature measurements, oxygen saturations and symptom scores were obtained using questionnaires and telephone interviews. Based on a National Institute of Health (NIH)-endorsed Protocol to research Patient Experience of COVID-19, we collected longitudinal severity scores of five symptoms (cough, shortness of breath, fatigue, headaches and anosmia) and general unwellness on a four-point ordinal scale modelled on performance status scoring. All data are reported at the patient level. Longitudinal combined normalized symptom scores were statistically compared. [0029] Ten consecutive patients with COVID-19 who self-administered high-dose oral famotidine were identified. The most frequently used famotidine regimen was 80 mg three times daily (n=6) for a median of 11 days (range: 5-21 days). Famotidine was well tolerated. All patients reported marked improvements of disease related symptoms after starting famotidine. The combined symptom score improved significantly within 24 hours of starting famotidine and peripheral oxygen saturation (n=2) and device recorded activity (n=l) increased.

[0030] Conclusions: The results of this case series suggest that high-dose oral famotidine is well tolerated and associated with improved patient-reported outcomes in non-hospitalized patients with COVID-19.

[0031] Additional objects and advantages of the present disclosure will be apparent from the description or may be learned by practice of the present disclosure. The objects and advantages of the present disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the specification and the appended claims. It is to be understood that the foregoing general description is exemplary and explanatory only and is not limiting of the invention as claimed.

[0032] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the true scope and spirit of the invention being indicated by the claims that follow.

[0033] It will be recognized by those skilled in the art that changes may be made to the above- described embodiments of the invention without departing from the broad inventive concepts hereof. The present invention is not limited to the specific embodiments disclosed herein, but it is intended to cover all modifications which are within the scope and spirit of the invention as defined by the appended claims.

Claims

Claims:

1. A composition comprising famotidine or famotidine analogs thereof for treating SARS- CoV-2 virus infection.

2. The composition of claim 1, wherein famotidine or analogs thereof inhibit SARS-CoV-2 virus infection.

3. The composition of claim 1, wherein famotidine is 3-[(2-guanidinothiazol-4- yl)methylsulfanyl]-N'-sulfamoyl-propanamidine or N'-(Aminosulfonyl)-3-([2- (diaminomethyleneamino)-4-thiazolyl]methylthio)propanamidine.

4. The composition of claim 1, wherein a famotidine analog is at least one of FAMOl 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N- sulfamoylpropanamide,

FAM05 3-[[2-[(N'-methylcarbamimidoyl)amino]-l,3-thiazol-4-yl]methylsulfanyl]-

N'-sulfamoylpropanimidamide,

FAM012 3-[[2-[(E)-hydrazinylmethylideneamino]-l,3-thiazol-4-yl]methylsulfanyl]-

N'-sulfamoylpropanimidamide, FAM013 Famotidine cyanoamidine,

FAM014 N'-cyano-3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- y 1 ] methyl sulfany 1 ] propanimi dami de,

FAM015 3-((2-(Diaminomethyleneamino)thiazol-4- yl)methylthio)propanimidamide,

FAMO30 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(trifluoromethylsulfonyl)propanimidamide,

FAM034 3-[({2-[(diaminomethylidene)amino]-l,3-thiazol-4-yl}methyl)sulfanyl]-

N'-sulfamoylpropanimidamide, FAM036 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM037 Famotidine hydrochloride,

FAM049 [[l-Arnino-3-[[2-(diarninomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]propylidene]amino]sulfonylazanide,

FAM056 3-[(2-Guanidinothiazol-4-yl)methylthio]propionamidoxime,

FAM064 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylprop-2-enimidamide, FAM067 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-3- methylsulfonylpropanimidamide,

FAM072 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(hydroxymethyl)-N-sulfamoylpropanimidamide,

F AM073 2- [2- [ [2-(Di aminomethylideneamino)- 1 ,3 -thiazol-4- yl]methylsulfanyl]ethyl]-l-(methylsulfamoyl)guanidine,

FAM074 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(trifluoromethylsulfonyl)propanimidamide,

FAM079 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(hydroxymethyl)-N-sulfamoylpropanimidamide,

FAM084 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(dimethylsulfamoyl)propanimidamide,

FAM085 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N,N'- disulfamoylpropanimidamide, FAM086 2-[4-[2-(l, 1-Di oxo-3, 6-dihydro-2H- 1,2,4, 6-thiatriazin-5- yl)ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

FAMOIOI 4-[[(3Z)-3-amino-3-(hydroxysulfonimidoyl)iminopropyl]sulfanylmethyl]-

2-(diaminomethylideneamino)-l,3-thiazole,

F AMO 104 2-[4-[2-[(4-amino- 1 , 1 -dioxo- 1 ,2, 5-thiadiazol-3 - ylidene)amino]ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine, FAMO105 3-[(S)-[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]- N'-sulfamoylpropanimidamide,

FAMO120 3-[((2-((aminoiminomethyl)amino)-4-thiazolyl)methyl)thio]-N'- (aminosulfonyl)propaneimidamide, FAM0121 4-[[(3Z)-3-amino-3-(hydroxysulfonimidoyl)iminopropyl]sulfanylmethyl]- 2-(diaminomethylideneamino)-l,3-thiazole,

FAM0131 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]-N'- sulfamoylpropanimidamide, or

5. The composition of claim 2 wherein the inhibitor of coronavirus SARS-CoV-2 inhibits PLpro (papain-like protease).

6. The composition of claim 1 wherein the composition is a histamine receptor antagonist.

7. The composition of claim 1 wherein the composition is an antiviral.

8. The composition of claim 7 wherein the antiviral composition is a histamine H2 receptor antagonist.

9. A method for treating coronavirus using the composition of claim 1.

10. A method for treating coronavirus using a pharmaceutical formulation comprising an effective amount of famotidine or related analogs and administering the pharmaceutical formulation to a patient in need thereof.

11. The composition of claim 7 wherein the antiviral composition is an oral tablet or capsule or an intravenous solution or suspension.

12. An antiviral composition including famotidine, 3-[(2-guanidinothiazol-4- yl)methylsulfanyl]-N'-sulfamoyl-propanamidine or N'-(Aminosulfonyl)-3-([2- (diaminomethyleneamino)-4-thiazolyl]methylthio)propanamidine, or at least one of a famotidine analog FAMOl 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4- yl]methylsulfanyl]-N-sulfamoylpropanamide,

FAM05 3-[[2-[(N'-methylcarbamimidoyl)amino]-l,3-thiazol-4-yl]methylsulfanyl]-

N'-sulfamoylpropanimidamide,

FAM012 3-[[2-[(E)-hydrazinylmethylideneamino]-l,3-thiazol-4-yl]methylsulfanyl]-

N'-sulfamoylpropanimidamide,

FAMOl 3 Famotidine cyanoamidine,

BO FAM015 3-((2-(Diaminomethyleneamino)thiazol-4- yl)methylthio)propanimidamide,

FAMO30 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(trifluoromethylsulfonyl)propanimidamide,

FAM034 3-[({2-[(diaminomethylidene)amino]-l,3-thiazol-4-yl}methyl)sulfanyl]-

N'-sulfamoylpropanimidamide,

FAM037 Famotidine hydrochloride, FAM042 3-[[2-[bis(dideuterioamino)methylideneamino]-5-deuterio-l,3-thiazol-4- yl]methylsulfanyl]-N,N-dideuterio-N'-(dideuteriosulfamoyl)propanimidamide,

FAM056 3-[(2-Guanidinothiazol-4-yl)methylthio]propionamidoxime,

FAM068 N'-[4-[[(3E)-3-(Hydrazinesulfonylimino)propyl]sulfanylmethyl]-l,3- thi azol -2-y 1 ] ethanimi dami de, FAMO70 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide,

FAM072 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(hydroxymethyl)-N-sulfamoylpropanimidamide,

FAM074 3-[[2-(diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(trifluoromethylsulfonyl)propanimidamide,

FAM079 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(hydroxymethyl)-N-sulfamoylpropanimidamide,

FAM084 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'-

(dimethylsulfamoyl)propanimidamide,

BB FAM089 [2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate,

FAMO101 4-[[(3Z)-3-amino-3-(hydroxysulfonimidoyl)iminopropyl]sulfanylmethyl]-

2-(diaminomethylideneamino)-l,3-thiazole,

FAMO105 3-[(S)-[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfmyl]-

N'-sulfamoylpropanimidamide,

F AMO 106 [1 -amino-3 -[[2-[(E)- 1 -aminoethylideneamino]- 1 ,3 -thiazol-4- yl]methylsulfanyl]propylidene]urea, FAMO107 [2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methyl N'- sulfamoylcarbamimidothioate,

FAM0122 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- sulfamoylpropanimidamide, F AMO 123 2-[4-[2-[(4- Amino- 1 , 1 -dioxo- 1 ,2, 5-thiadiazol-3 - ylidene)amino]ethylsulfanylmethyl]-l,3-thiazol-2-yl]guanidine,

FAM0132 3-[[2-(Diaminomethylideneamino)-l,3-thiazol-4-yl]methylsulfanyl]-N'- hydroxypropanimidamide, wherein the antiviral composition is a histamine H2 antagonist, the antiviral composition is an inhibitor of coronavirus SARS-CoV-2, the antiviral composition is an oral tablet or capsule or an intravenous solution or suspension.