Efficacy of Host Cell Serine Protease Inhibitor MM3122 Against SARS-CoV-2 for Treatment and Prevention of COVID-19

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2024 Apr 9

PMID 38593045

Authors

Adrianus C M Boon

Traci L Bricker

Ethan J Fritch

Sarah R Leist

Kendra Gully

Ralph S Baric

Rachel L Graham

Brigid V Troan

Matthew Mahoney

James W Janetka

Affiliations

Soon will be listed here.

Abstract

Importance: SARS-CoV-2 and other emerging RNA coronaviruses are a present and future threat in causing widespread endemic and pandemic infection and disease. In this paper, we have shown that the novel host cell protease inhibitor, MM3122, blocks SARS-CoV-2 viral replication and is efficacious as both a prophylactic and a therapeutic drug for the treatment of COVID-19 given intraperitoneally in mice. Targeting host proteins and pathways in antiviral therapy is an underexplored area of research, but this approach promises to avoid drug resistance by the virus, which is common in current antiviral treatments.

Citing Articles

Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin.

Mahoney M, Helander J, Kooner A, Norman M, Damalanka V, De Bona P Protein Sci. 2024; 33(8):e5110.

PMID: 39073183 PMC: 11284329. DOI: 10.1002/pro.5110.

Rational Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket.

Desgagne M, Desilets A, Ferkova S, Lepage M, Perreault O, Joushomme A J Med Chem. 2024; 67(15):12969-12983.

PMID: 39028865 PMC: 11321340. DOI: 10.1021/acs.jmedchem.4c00922.

References

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

Bottcher-Friebertshauser E, Freuer C, Sielaff F, Schmidt S, Eickmann M, Uhlendorff J . Cleavage of influenza virus hemagglutinin by airway proteases TMPRSS2 and HAT differs in subcellular localization and susceptibility to protease inhibitors. J Virol. 2010; 84(11):5605-14. PMC: 2876594. DOI: 10.1128/JVI.00140-10. View

Song W, Sun S, Feng Y, Liu L, Gao T, Xian S . Efficacy and safety of baricitinib in patients with severe COVID-19: A systematic review and meta-analysis. Medicine (Baltimore). 2023; 102(48):e36313. PMC: 10695502. DOI: 10.1097/MD.0000000000036313. View

Paszti-Gere E, Czimmermann E, Ujhelyi G, Balla P, Maiwald A, Steinmetzer T . In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells. J Enzyme Inhib Med Chem. 2016; 31(sup2):123-129. DOI: 10.1080/14756366.2016.1193732. View

Lambertz R, Gerhauser I, Nehlmeier I, Gartner S, Winkler M, Leist S . H2 influenza A virus is not pathogenic in Tmprss2 knock-out mice. Virol J. 2020; 17(1):56. PMC: 7178614. DOI: 10.1186/s12985-020-01323-z. View

Shirato K, Kawase M, Matsuyama S . Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J Virol. 2013; 87(23):12552-61. PMC: 3838146. DOI: 10.1128/JVI.01890-13. View

Walmsley T, Rose A, John R, Wei D, Hlavka J, Machado J . Macroeconomic consequences of the COVID-19 pandemic. Econ Model. 2022; 120:106147. PMC: 9768433. DOI: 10.1016/j.econmod.2022.106147. View

Vaarala M, Porvari K, Kellokumpu S, Kyllonen A, Vihko P . Expression of transmembrane serine protease TMPRSS2 in mouse and human tissues. J Pathol. 2001; 193(1):134-40. DOI: 10.1002/1096-9896(2000)9999:9999<::AID-PATH743>3.0.CO;2-T. View

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S . SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181(2):271-280.e8. PMC: 7102627. DOI: 10.1016/j.cell.2020.02.052. View

10.

Fuentes-Prior P . Priming of SARS-CoV-2 S protein by several membrane-bound serine proteinases could explain enhanced viral infectivity and systemic COVID-19 infection. J Biol Chem. 2020; 296:100135. PMC: 7834812. DOI: 10.1074/jbc.REV120.015980. View

11.

Tarnow C, Engels G, Arendt A, Schwalm F, Sediri H, Preuss A . TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J Virol. 2014; 88(9):4744-51. PMC: 3993819. DOI: 10.1128/JVI.03799-13. View

12.

Yang H, Lin X, Yu Q, Awadasseid A, Zhang W . Repurposing and discovery of transmembrane serine protease 2 (TMPRSS2) inhibitors as prophylactic therapies for new coronavirus disease 2019 (COVID-19). Pharmazie. 2024; 78(11):217-224. DOI: 10.1691/ph.2023.3578. View

13.

Dinnon 3rd K, Leist S, Okuda K, Dang H, Fritch E, Gully K . SARS-CoV-2 infection produces chronic pulmonary epithelial and immune cell dysfunction with fibrosis in mice. Sci Transl Med. 2022; 14(664):eabo5070. PMC: 9273046. DOI: 10.1126/scitranslmed.abo5070. View

14.

Shapira T, Monreal I, Dion S, Buchholz D, Imbiakha B, Olmstead A . A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature. 2022; 605(7909):340-348. PMC: 9095466. DOI: 10.1038/s41586-022-04661-w. View

15.

Leist S, Dinnon 3rd K, Schafer A, Tse L, Okuda K, Hou Y . A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice. Cell. 2020; 183(4):1070-1085.e12. PMC: 7510428. DOI: 10.1016/j.cell.2020.09.050. View

16.

Gomes C, Fernandes D, Casimiro F, da Mata G, Passos M, Varela P . Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics. Front Cell Infect Microbiol. 2020; 10:589505. PMC: 7753008. DOI: 10.3389/fcimb.2020.589505. View

17.

Rahbar Saadat Y, Hosseiniyan Khatibi S, Zununi Vahed S, Ardalan M . Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza. Front Mol Biosci. 2021; 8:725528. PMC: 8435734. DOI: 10.3389/fmolb.2021.725528. View

18.

Meyer D, Sielaff F, Hammami M, Bottcher-Friebertshauser E, Garten W, Steinmetzer T . Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation. Biochem J. 2013; 452(2):331-43. DOI: 10.1042/BJ20130101. View

19.

Baron J, Tarnow C, Mayoli-Nussle D, Schilling E, Meyer D, Hammami M . Matriptase, HAT, and TMPRSS2 activate the hemagglutinin of H9N2 influenza A viruses. J Virol. 2012; 87(3):1811-20. PMC: 3554176. DOI: 10.1128/JVI.02320-12. View

20.

Corbett K, Edwards D, Leist S, Abiona O, Boyoglu-Barnum S, Gillespie R . SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature. 2020; 586(7830):567-571. PMC: 7581537. DOI: 10.1038/s41586-020-2622-0. View