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Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

ABSTRACT: COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to inhibit coronavirus family 3CL protease activity with selectivity over human host protease targets. Furthermore, we show that PF-00835231 has additive/synergistic activity in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of PF-07304814 as a potential COVID-19 treatment.

SUBMITTER: Boras B

PROVIDER: S-EPMC8523698 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

Boras Britton B Jones Rhys M RM Anson Brandon J BJ Arenson Dan D Aschenbrenner Lisa L Bakowski Malina A MA Beutler Nathan N Binder Joseph J Chen Emily E Eng Heather H Hammond Holly H Hammond Jennifer J Haupt Robert E RE Hoffman Robert R Kadar Eugene P EP Kania Rob R Kimoto Emi E Kirkpatrick Melanie G MG Lanyon Lorraine L Lendy Emma K EK Lillis Jonathan R JR Logue James J Luthra Suman A SA Ma Chunlong C Mason Stephen W SW McGrath Marisa E ME Noell Stephen S Obach R Scott RS O' Brien Matthew N MN O'Connor Rebecca R Ogilvie Kevin K Owen Dafydd D Pettersson Martin M Reese Matthew R MR Rogers Thomas F TF Rosales Romel R Rossulek Michelle I MI Sathish Jean G JG Shirai Norimitsu N Steppan Claire C Ticehurst Martyn M Updyke Lawrence W LW Weston Stuart S Zhu Yuao Y White Kris M KM García-Sastre Adolfo A Wang Jun J Chatterjee Arnab K AK Mesecar Andrew D AD Frieman Matthew B MB Anderson Annaliesa S AS Allerton Charlotte C

Nature communications 20211018 1

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. PF-00835231, a 3CL protease inhibitor, has exhibited potent in vitro antiviral activity against SARS-CoV-2 as a single agent. Here we report, the design and characterization of a phosphate prodrug PF-07304814 to enable the delivery and projected sustained systemic exposure in human of PF-00835231 to ...[more]

PMID: 34663813

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Project description:We describe a mammalian cell-based assay to identify coronavirus 3CL protease (3CLpro) inhibitors. This assay is based on rescuing protease-mediated cytotoxicity and does not require live virus. By enabling the facile testing of compounds across a range of 15 distantly related coronavirus 3CLpro enzymes, we identified compounds with broad 3CLpro-inhibitory activity. We also adapted the assay for use in compound screening and in doing so uncovered additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CLpro inhibitors. We observed strong concordance between data emerging from this assay and those obtained from live-virus testing. The reported approach democratizes the testing of 3CLpro inhibitors by developing a simplified method for identifying coronavirus 3CLpro inhibitors that can be used by the majority of laboratories, rather than the few with extensive biosafety infrastructure. We identified two lead compounds, GC376 and compound 4, with broad activity against all 3CL proteases tested, including 3CLpro enzymes from understudied zoonotic coronaviruses. IMPORTANCE Multiple coronavirus pandemics have occurred over the last 2 decades. This has highlighted a need to be proactive in the development of therapeutics that can be readily deployed in the case of future coronavirus pandemics. We developed and validated a simplified cell-based assay for the identification of chemical inhibitors of 3CL proteases encoded by a wide range of coronaviruses. This assay is reporter free, does not require specialized biocontainment, and is optimized for performance in high-throughput screening. By testing reported 3CL protease inhibitors against a large collection of 3CL proteases with variable sequence similarity, we identified compounds with broad activity against 3CL proteases and uncovered structural insights into features that contribute to their broad activity. Furthermore, we demonstrated that this assay is suitable for identifying chemical inhibitors of proteases from families other than 3CL proteases.

Dataset Information

Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

Publications

Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.

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