A comparative analysis of SARS-CoV-2 antivirals in human airway models characterizes 3CL pro inhibitor PF-00835231 as a potential new treatment for COVID-19.
العنوان: | A comparative analysis of SARS-CoV-2 antivirals in human airway models characterizes 3CL pro inhibitor PF-00835231 as a potential new treatment for COVID-19. |
---|---|
المؤلفون: | de Vries M; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA., Mohamed AS; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA., Prescott RA; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA.; Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York 10016, USA., Valero-Jimenez AM; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA., Desvignes L; Department of Medicine, New York University Grossman School of Medicine, New York 10016, USA.; Office of Science & Research, NYU Langone Health, New York 10016, USA., O'Connor R; Pfizer Discovery Sciences, Groton, CT 06340, USA., Steppan C; Pfizer Discovery Sciences, Groton, CT 06340, USA., Devlin JC; Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York 10016, USA.; Institute of Systems Genetics, New York University Grossman School of Medicine, New York 10016, USA., Ivanova E; Department of Pathology, New York University Grossman School of Medicine, New York 10016, USA., Herrera A; Department of Pathology, New York University Grossman School of Medicine, New York 10016, USA., Schinlever A; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA.; Vilcek Institute of Graduate Biomedical Sciences, New York University Grossman School of Medicine, New York 10016, USA., Loose P; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA., Ruggles K; Institute of Systems Genetics, New York University Grossman School of Medicine, New York 10016, USA., Koralov SB; Department of Pathology, New York University Grossman School of Medicine, New York 10016, USA., Anderson AS; Pfizer Vaccine Research and Development, Pearl River, NY 10695, USA., Binder J; Pfizer Oncology Research and Development, San Diego, CA 92128, USA., Dittmann M; Department of Microbiology, New York University Grossman School of Medicine, New York 10016, USA. |
المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2021 Feb 19. Date of Electronic Publication: 2021 Feb 19. |
نوع المنشور: | Preprint |
اللغة: | English |
بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
مستخلص: | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19). There is a dire need for novel effective antivirals to treat COVID-19, as the only approved direct-acting antiviral to date is remdesivir, targeting the viral polymerase complex. A potential alternate target in the viral life cycle is the main SARS-CoV-2 protease 3CL pro (M pro ). The drug candidate PF-00835231 is the active compound of the first anti-3CL pro regimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the pre-clinical 3CL pro inhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549 +ACE2 cells). We find PF-00835231 with at least similar or higher potency than remdesivir or GC-376. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps in A549 +ACE2 cells and validates PF-00835231's early time of action. In a model of the human polarized airway epithelium, both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 at low micromolar concentrations. Finally, we show that the efflux transporter P-glycoprotein, which was previously suggested to diminish PF-00835231's efficacy based on experiments in monkey kidney Vero E6 cells, does not negatively impact PF-00835231 efficacy in either A549 +ACE2 cells or human polarized airway epithelial cultures. Thus, our study provides in vitro evidence for the potential of PF-00835231 as an effective SARS-CoV-2 antiviral and addresses concerns that emerged based on prior studies in non-human in vitro models. Competing Interests: Competing interests M. D. received a contract from Pfizer Inc. to support the studies reported herein. These authors are employees of Pfizer Inc. and hold stock in Pfizer Inc: Joseph Binder, Annaliesa Anderson, Claire Steppan, Rebecca O’Connor. |
التعليقات: | Update in: J Virol. 2021 Feb 23;:. (PMID: 33622961) |
References: | Development. 2019 Oct 23;146(20):. (PMID: 31558434) Clin Infect Dis. 2019 Jan 7;68(2):177-187. (PMID: 30052811) Sci Transl Med. 2020 Apr 29;12(541):. (PMID: 32253226) mBio. 2018 Mar 6;9(2):. (PMID: 29511076) Antimicrob Agents Chemother. 2004 Apr;48(4):1073-81. (PMID: 15047504) N Engl J Med. 2020 Mar 19;382(12):1177-1179. (PMID: 32074444) Science. 2020 Apr 24;368(6489):409-412. (PMID: 32198291) Nat Microbiol. 2020 Apr;5(4):536-544. (PMID: 32123347) J Antimicrob Chemother. 2011 May;66(5):959-63. (PMID: 21406435) Nature. 2020 Jun;582(7811):289-293. (PMID: 32272481) Science. 2020 Jun 19;368(6497):1331-1335. (PMID: 32321856) Lancet Respir Med. 2020 Jul;8(7):687-695. (PMID: 32386571) J Virol. 2010 Jul;84(13):6894-8. (PMID: 20427532) Nature. 2021 Apr;592(7852):116-121. (PMID: 33106671) N Engl J Med. 2020 May 7;382(19):1787-1799. (PMID: 32187464) N Engl J Med. 2020 Aug 6;383(6):590-592. (PMID: 32402155) J Virol. 1999 Jan;73(1):177-85. (PMID: 9847320) Antiviral Res. 2020 Jun;178:104793. (PMID: 32283108) Virol J. 2009 Dec 24;6:230. (PMID: 20034394) Biochem J. 2020 Mar 13;477(5):1009-1019. (PMID: 32083638) N Engl J Med. 2020 Feb 20;382(8):727-733. (PMID: 31978945) Virology. 1996 Jul 15;221(2):325-34. (PMID: 8661443) J Med Chem. 2020 Nov 12;63(21):12725-12747. (PMID: 33054210) Cell Res. 2020 Aug;30(8):678-692. (PMID: 32541865) Nat Med. 2020 Jun;26(6):842-844. (PMID: 32398875) Nature. 2021 Mar;591(7849):293-299. (PMID: 33494095) Blood. 1999 Jan 15;93(2):599-606. (PMID: 9885221) Science. 2020 Jul 17;369(6501):297-301. (PMID: 32471856) Sci Rep. 2020 Jul 27;10(1):12493. (PMID: 32719454) J Exp Med. 2020 May 4;217(5):. (PMID: 32302378) Nature. 2020 May;581(7809):465-469. (PMID: 32235945) Viruses. 2020 Jan 24;12(2):. (PMID: 31991541) Immunity. 2017 Dec 19;47(6):1182-1196.e10. (PMID: 29262351) Clin Infect Dis. 2020 Aug 14;71(4):1092-1094. (PMID: 31538179) Oncoimmunology. 2018 Sep 6;7(12):e1499388. (PMID: 30524890) PLoS Pathog. 2019 Nov 4;15(11):e1007634. (PMID: 31682641) Nat Protoc. 2011 Jun;6(6):925-33. (PMID: 21637207) PLoS Biol. 2021 Mar 17;19(3):e3001143. (PMID: 33730024) Cell. 2019 Jun 13;177(7):1888-1902.e21. (PMID: 31178118) Genome Biol. 2018 Dec 19;19(1):224. (PMID: 30567574) Nat Struct Mol Biol. 2020 Jun;27(6):529-532. (PMID: 32382072) Cell Rep. 2020 Mar 24;30(12):4250-4265.e6. (PMID: 32209482) Cell. 2020 May 28;181(5):1036-1045.e9. (PMID: 32416070) Cell Rep. 2020 Jul 21;32(3):107940. (PMID: 32668216) J Virol. 2012 Nov;86(21):11754-62. (PMID: 22915796) J Virol. 2014 Oct;88(20):11886-98. (PMID: 25100843) Blood. 1992 Dec 1;80(11):2735-9. (PMID: 1360267) Respir Res. 2013 Dec 03;14:135. (PMID: 24298994) N Engl J Med. 2020 Jun 11;382(24):2327-2336. (PMID: 32275812) J Pharm Sci. 2007 Jun;96(6):1609-18. (PMID: 17094122) Nat Commun. 2020 Aug 27;11(1):4282. (PMID: 32855413) Cancer Res. 2014 Jan 15;74(2):598-608. (PMID: 24305879) Gut Liver. 2017 Sep 15;11(5):590-603. (PMID: 28494575) Nature. 2020 Jul;583(7816):459-468. (PMID: 32353859) Science. 2020 Dec 18;370(6523):1464-1468. (PMID: 33184236) J Biol Chem. 2020 May 15;295(20):6785-6797. (PMID: 32284326) Nat Microbiol. 2020 Nov;5(11):1403-1407. (PMID: 32669681) Lancet Microbe. 2020 May;1(1):e14-e23. (PMID: 32835326) |
معلومات مُعتمدة: | P30 CA016087 United States CA NCI NIH HHS; R01 AI143639 United States AI NIAID NIH HHS; R01 HL125816 United States HL NHLBI NIH HHS; R21 AI139374 United States AI NIAID NIH HHS |
تواريخ الأحداث: | Date Created: 20200902 Latest Revision: 20240211 |
رمز التحديث: | 20240211 |
مُعرف محوري في PubMed: | PMC7457613 |
DOI: | 10.1101/2020.08.28.272880 |
PMID: | 32869028 |
قاعدة البيانات: | MEDLINE |
DOI: | 10.1101/2020.08.28.272880 |
---|