دورية أكاديمية
Efficacy of host cell serine protease inhibitor MM3122 against SARS-CoV-2 for treatment and prevention of COVID-19.
| العنوان: | Efficacy of host cell serine protease inhibitor MM3122 against SARS-CoV-2 for treatment and prevention of COVID-19. |
|---|---|
| المؤلفون: | Boon ACM; Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA., Bricker TL; Department of Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA., Fritch EJ; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Leist SR; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA., Gully K; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA., Baric RS; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA., Graham RL; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA., Troan BV; Inotiv, West Lafayette, Indiana, USA., Mahoney M; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, Missouri, USA., Janetka JW; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, Missouri, USA. |
| المصدر: | Journal of virology [J Virol] 2024 May 14; Vol. 98 (5), pp. e0190323. Date of Electronic Publication: 2024 Apr 09. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Society For Microbiology Original Publication: Baltimore, American Society for Microbiology. |
| مواضيع طبية MeSH: | Antiviral Agents*/pharmacology , COVID-19 Drug Treatment* , SARS-CoV-2*/drug effects , SARS-CoV-2*/physiology , Serine Proteinase Inhibitors*/pharmacology , Serine Proteinase Inhibitors*/therapeutic use , Virus Replication*/drug effects , Oligopeptides*/pharmacology , Benzothiazoles*/pharmacology, Animals ; Female ; Humans ; Mice ; Chlorocebus aethiops ; COVID-19/virology ; Disease Models, Animal ; Lung/virology ; Lung/pathology ; Lung/drug effects ; Peptidomimetics/pharmacology ; Serine Endopeptidases/metabolism ; Vero Cells |
| مستخلص: | We developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases, including transmembrane protease serine 2 (TMPRSS2), matriptase, and hepsin. TMPRSS2 is a membrane-associated protease that is highly expressed in the upper and lower respiratory tracts and is utilized by SARS-CoV-2 and other viruses to proteolytically process their glycoproteins, enabling host cell entry, replication, and dissemination of new virus particles. We have previously shown that compound MM3122 exhibited subnanomolar potency against all three proteases and displayed potent antiviral effects against SARS-CoV-2 in a cell viability assay. Herein, we demonstrate that MM3122 potently inhibits viral replication in human lung epithelial cells and is also effective against the EG.5.1 variant of SARS-CoV-2. Furthermore, we evaluated MM3122 in a mouse model of COVID-19 and demonstrated that MM3122 administered intraperitoneally (IP) before (prophylactic) or after (therapeutic) SARS-CoV-2 infection had significant protective effects against weight loss and lung congestion and reduced pathology. Amelioration of COVID-19 disease was associated with a reduction in proinflammatory cytokine and chemokine production after SARS-CoV-2 infection. Prophylactic, but not therapeutic, administration of MM3122 also reduced virus titers in the lungs of SARS-CoV-2-infected mice. Therefore, MM3122 is a promising lead candidate small-molecule drug for the treatment and prevention of infections caused by SARS-CoV-2 and other coronaviruses. 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. Competing Interests: The Boon laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, GreenLight Biosciences Inc., Moderna Inc., and Nano targeting & Therapy Biopharma Inc. The Boon laboratory has received funding support from AbbVie Inc., for the commercial development of SARS-CoV-2 mAb. |
| التعليقات: | Update of: bioRxiv. 2024 Feb 12:2024.02.09.579701. doi: 10.1101/2024.02.09.579701. (PMID: 38405752) |
| References: | Nature. 2020 Mar;579(7798):270-273. (PMID: 32015507) J Virol. 2010 Jun;84(11):5605-14. (PMID: 20237084) Medicine (Baltimore). 2023 Dec 1;102(48):e36313. (PMID: 38050265) J Enzyme Inhib Med Chem. 2016;31(sup2):123-129. (PMID: 27277342) Virol J. 2020 Apr 22;17(1):56. (PMID: 32321537) J Virol. 2013 Dec;87(23):12552-61. (PMID: 24027332) Econ Model. 2023 Mar;120:106147. (PMID: 36570545) J Pathol. 2001 Jan;193(1):134-40. (PMID: 11169526) Cell. 2020 Apr 16;181(2):271-280.e8. (PMID: 32142651) J Biol Chem. 2021 Jan-Jun;296:100135. (PMID: 33268377) J Virol. 2014 May;88(9):4744-51. (PMID: 24522916) Pharmazie. 2023 Dec 4;78(11):217-224. (PMID: 38178286) Sci Transl Med. 2022 Sep 28;14(664):eabo5070. (PMID: 35857635) Nature. 2022 May;605(7909):340-348. (PMID: 35344983) Cell. 2020 Nov 12;183(4):1070-1085.e12. (PMID: 33031744) Front Cell Infect Microbiol. 2020 Dec 08;10:589505. (PMID: 33364201) Front Mol Biosci. 2021 Aug 30;8:725528. (PMID: 34527703) Biochem J. 2013 Jun 1;452(2):331-43. (PMID: 23527573) J Virol. 2013 Feb;87(3):1811-20. (PMID: 23192872) Nature. 2020 Oct;586(7830):567-571. (PMID: 32756549) Nature. 2023 Dec;624(7990):207-214. (PMID: 37879362) Nature. 2023 Jan;613(7942):130-137. (PMID: 36517599) Sci Transl Med. 2017 Jun 28;9(396):. (PMID: 28659436) Future Med Chem. 2019 Apr;11(7):743-769. (PMID: 30945556) J Virol. 2006 Oct;80(19):9896-8. (PMID: 16973594) Sci Immunol. 2020 May 13;5(47):. (PMID: 32404436) ChemMedChem. 2024 Jan 15;19(2):e202300458. (PMID: 37864572) Cancer Discov. 2014 Nov;4(11):1310-25. (PMID: 25122198) J Virol. 2010 Oct;84(19):10016-25. (PMID: 20631123) J Virol. 2013 Jun;87(11):6150-60. (PMID: 23536651) J Virol. 2013 Nov;87(21):11930-5. (PMID: 23966399) Proc Natl Acad Sci U S A. 2021 Oct 26;118(43):. (PMID: 34635581) J Virol. 2011 May;85(9):4122-34. (PMID: 21325420) J Virol. 2016 Apr 14;90(9):4298-4307. (PMID: 26889029) Sci Transl Med. 2020 Apr 29;12(541):. (PMID: 32253226) Cancer Res. 2001 Feb 15;61(4):1686-92. (PMID: 11245484) FEBS J. 2017 May;284(10):1421-1436. (PMID: 27870503) J Virol. 2013 Apr;87(8):4237-51. (PMID: 23365447) ACS Pharmacol Transl Sci. 2020 Sep 07;3(5):997-1007. (PMID: 33062952) EBioMedicine. 2021 Mar;65:103255. (PMID: 33676899) Front Pharmacol. 2023 Oct 19;14:1265541. (PMID: 37927607) Nat Chem Biol. 2022 Sep;18(9):963-971. (PMID: 35676539) Nat Med. 2021 Apr;27(4):717-726. (PMID: 33664494) Infection. 2021 Jun;49(3):401-410. (PMID: 33389708) Influenza Other Respir Viruses. 2020 Mar;14(2):189-195. (PMID: 31820577) Lancet Respir Med. 2023 Dec;11(12):1064-1074. (PMID: 37977159) J Virol. 2011 Dec;85(24):13363-72. (PMID: 21994442) PLoS Pathog. 2013;9(12):e1003774. (PMID: 24348248) Int J Cancer. 2001 Dec 1;94(5):705-10. (PMID: 11745466) Science. 2023 Nov 10;382(6671):649-650. (PMID: 37943911) J Virol. 2013 May;87(10):5502-11. (PMID: 23468491) Life Sci Alliance. 2020 Jul 23;3(9):. (PMID: 32703818) Eur J Med Chem. 2022 Aug 5;238:114437. (PMID: 35635944) |
| معلومات مُعتمدة: | 75N93021C00016 United States AI NIAID NIH HHS; HHSN272201700036I/75N93020F00001 HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID); P30 CA091842 United States CA NCI NIH HHS; R01 AI169022 United States AI NIAID NIH HHS; BJHF 4984 Foundation for Barnes-Jewish Hospital (FBJH); SCC P30CA091842 Alvin J. Siteman Cancer Center (SCC); R01 AI169022, 75N93021C00016 HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) |
| فهرسة مساهمة: | Keywords: COVID-19; SARS-CoV-2; TMPRSS2; protease inhibitor |
| المشرفين على المادة: | 0 (Antiviral Agents) 0 (Peptidomimetics) EC 3.4.21.- (Serine Endopeptidases) 0 (Serine Proteinase Inhibitors) 0 (Ac-GQFR-kbt) 0 (Oligopeptides) 0 (Benzothiazoles) |
| تواريخ الأحداث: | Date Created: 20240409 Date Completed: 20240514 Latest Revision: 20240604 |
| رمز التحديث: | 20240605 |
| مُعرف محوري في PubMed: | PMC11092322 |
| DOI: | 10.1128/jvi.01903-23 |
| PMID: | 38593045 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-5514 |
|---|---|
| DOI: | 10.1128/jvi.01903-23 |