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Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19.
Boras, Britton; Jones, Rhys M; Anson, Brandon J; Arenson, Dan; Aschenbrenner, Lisa; Bakowski, Malina A; Beutler, Nathan; Binder, Joseph; Chen, Emily; Eng, Heather; Hammond, Holly; Hammond, Jennifer; Haupt, Robert E; Hoffman, Robert; Kadar, Eugene P; Kania, Rob; Kimoto, Emi; Kirkpatrick, Melanie G; Lanyon, Lorraine; Lendy, Emma K; Lillis, Jonathan R; Logue, James; Luthra, Suman A; Ma, Chunlong; Mason, Stephen W; McGrath, Marisa E; Noell, Stephen; Obach, R Scott; O' Brien, Matthew N; O'Connor, Rebecca; Ogilvie, Kevin; Owen, Dafydd; Pettersson, Martin; Reese, Matthew R; Rogers, Thomas F; Rosales, Romel; Rossulek, Michelle I; Sathish, Jean G; Shirai, Norimitsu; Steppan, Claire; Ticehurst, Martyn; Updyke, Lawrence W; Weston, Stuart; Zhu, Yuao; White, Kris M; García-Sastre, Adolfo; Wang, Jun; Chatterjee, Arnab K; Mesecar, Andrew D; Frieman, Matthew B.
  • Boras B; Worldwide Research and Development, Pfizer Inc, La Jolla, CA, 92121, USA.
  • Jones RM; Worldwide Research and Development, Pfizer Inc, La Jolla, CA, 92121, USA. rhys.jones@pfizer.com.
  • Anson BJ; Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907, USA.
  • Arenson D; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Aschenbrenner L; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Bakowski MA; Calibr, a division of The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Beutler N; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Binder J; Worldwide Research and Development, Pfizer Inc, La Jolla, CA, 92121, USA.
  • Chen E; Calibr, a division of The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Eng H; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Hammond H; Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • Hammond J; Worldwide Research and Development, Pfizer Inc., Collegeville, PA, 19426, USA.
  • Haupt RE; Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • Hoffman R; Worldwide Research and Development, Pfizer Inc, La Jolla, CA, 92121, USA.
  • Kadar EP; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Kania R; Worldwide Research and Development, Pfizer Inc, La Jolla, CA, 92121, USA.
  • Kimoto E; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Kirkpatrick MG; Calibr, a division of The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Lanyon L; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Lendy EK; Department of Biochemistry, Purdue University, West Lafayette, IN, 47907, USA.
  • Lillis JR; Worldwide Research and Development, Pfizer Inc, Sandwich, CT13 9ND, UK.
  • Logue J; Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • Luthra SA; Worldwide Research and Development, Pfizer Inc, Cambridge, MA, 02139, USA.
  • Ma C; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA.
  • Mason SW; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • McGrath ME; Worldwide Research and Development, Pfizer Inc., Pearl River, NY, 10965, USA.
  • Noell S; Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • Obach RS; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • O' Brien MN; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • O'Connor R; Worldwide Research and Development, Pfizer Inc, Lake Forest, IL, 60045, USA.
  • Ogilvie K; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Owen D; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Pettersson M; Worldwide Research and Development, Pfizer Inc, Cambridge, MA, 02139, USA.
  • Reese MR; Worldwide Research and Development, Pfizer Inc, Cambridge, MA, 02139, USA.
  • Rogers TF; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Rosales R; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
  • Rossulek MI; UC San Diego Division of Infectious Diseases and Global Public Health, UC San Diego School of Medicine, La Jolla, CA, 92093, USA.
  • Sathish JG; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Shirai N; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Steppan C; Worldwide Research and Development, Pfizer Inc, Cambridge, MA, 02139, USA.
  • Ticehurst M; Worldwide Research and Development, Pfizer Inc., Pearl River, NY, 10965, USA.
  • Updyke LW; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Weston S; Worldwide Research and Development, Pfizer Inc, Groton, CT, 06340, USA.
  • Zhu Y; Worldwide Research and Development, Pfizer Inc, Sandwich, CT13 9ND, UK.
  • White KM; Worldwide Research and Development, Pfizer Inc, Cambridge, MA, 02139, USA.
  • García-Sastre A; Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
  • Wang J; Worldwide Research and Development, Pfizer Inc., Pearl River, NY, 10965, USA.
  • Chatterjee AK; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Mesecar AD; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Frieman MB; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Commun ; 12(1): 6055, 2021 10 18.
Article in English | MEDLINE | ID: covidwho-1475294
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pyrrolidinones / Coronavirus Protease Inhibitors / Coronavirus 3C Proteases / COVID-19 Drug Treatment / Indoles / Leucine Type of study: Experimental Studies / Prognostic study Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-26239-2

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pyrrolidinones / Coronavirus Protease Inhibitors / Coronavirus 3C Proteases / COVID-19 Drug Treatment / Indoles / Leucine Type of study: Experimental Studies / Prognostic study Language: English Journal: Nat Commun Journal subject: Biology / Science Year: 2021 Document Type: Article Affiliation country: S41467-021-26239-2