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Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19

View ORCID ProfileBritton Boras, View ORCID ProfileRhys M. Jones, View ORCID ProfileBrandon J. Anson, Dan Arenson, Lisa Aschenbrenner, View ORCID ProfileMalina A. Bakowski, View ORCID ProfileNathan Beutler, Joseph Binder, Emily Chen, View ORCID ProfileHeather Eng, Holly Hammond, Jennifer Hammond, Robert E. Haupt, View ORCID ProfileRobert Hoffman, Eugene P. Kadar, Rob Kania, View ORCID ProfileEmi Kimoto, Melanie G. Kirkpatrick, Lorraine Lanyon, View ORCID ProfileEmma K. Lendy, Jonathan R. Lillis, James Logue, Suman A. Luthra, View ORCID ProfileChunlong Ma, Stephen W. Mason, Marisa E. McGrath, Stephen Noell, View ORCID ProfileR. Scott Obach, View ORCID ProfileMatthew N. O’Brien, Rebecca O’Connor, Kevin Ogilvie, View ORCID ProfileDafydd Owen, Martin Pettersson, Matthew R Reese, Thomas F. Rogers, Michelle I. Rossulek, Jean G. Sathish, Norimitsu Shirai, View ORCID ProfileClaire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Stuart Weston, Yuao Zhu, View ORCID ProfileJun Wang, View ORCID ProfileArnab K. Chatterjee, View ORCID ProfileAndrew D. Mesecar, Matthew B. Frieman, View ORCID ProfileAnnaliesa S. Anderson, Charlotte Allerton
doi: https://doi.org/10.1101/2020.09.12.293498
Britton Boras
1Worldwide Research and Development, Pfizer Inc., La Jolla, CA 92121
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Rhys M. Jones
1Worldwide Research and Development, Pfizer Inc., La Jolla, CA 92121
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  • For correspondence: rhys.jones@pfizer.com
Brandon J. Anson
9Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907 USA
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Dan Arenson
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Lisa Aschenbrenner
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Malina A. Bakowski
11Calibr, a division of The Scripps Research Institute, La Jolla, CA 92037
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  • ORCID record for Malina A. Bakowski
Nathan Beutler
12Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037
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  • ORCID record for Nathan Beutler
Joseph Binder
1Worldwide Research and Development, Pfizer Inc., La Jolla, CA 92121
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Emily Chen
11Calibr, a division of The Scripps Research Institute, La Jolla, CA 92037
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Heather Eng
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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  • ORCID record for Heather Eng
Holly Hammond
14Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD 21201
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Jennifer Hammond
6Worldwide Research and Development, Pfizer Inc., Collegeville, PA 19426, USA
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Robert E. Haupt
14Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD 21201
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Robert Hoffman
1Worldwide Research and Development, Pfizer Inc., La Jolla, CA 92121
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Eugene P. Kadar
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Rob Kania
1Worldwide Research and Development, Pfizer Inc., La Jolla, CA 92121
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Emi Kimoto
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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  • ORCID record for Emi Kimoto
Melanie G. Kirkpatrick
11Calibr, a division of The Scripps Research Institute, La Jolla, CA 92037
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Lorraine Lanyon
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Emma K. Lendy
10Department of Biochemistry, Purdue University, West Lafayette, IN, 47907 USA
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  • ORCID record for Emma K. Lendy
Jonathan R. Lillis
7Worldwide Research and Development, Pfizer Inc., Sandwich, CT13 9ND, UK
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James Logue
14Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD 21201
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Suman A. Luthra
3Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139
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Chunlong Ma
8Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721
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  • ORCID record for Chunlong Ma
Stephen W. Mason
2Worldwide Research and Development, Pfizer Inc., Pearl River, NY 10965
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Marisa E. McGrath
14Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD 21201
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Stephen Noell
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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R. Scott Obach
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Matthew N. O’Brien
5Worldwide Research and Development, Pfizer Inc., Lake Forest, IL 60045
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Rebecca O’Connor
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Kevin Ogilvie
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Dafydd Owen
3Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139
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Martin Pettersson
3Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139
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Matthew R Reese
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Thomas F. Rogers
12Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037
13UC San Diego Division of Infectious Diseases and Global Public Health, UC San Diego School of Medicine, La Jolla, CA 92093
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Michelle I. Rossulek
3Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139
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Jean G. Sathish
2Worldwide Research and Development, Pfizer Inc., Pearl River, NY 10965
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Norimitsu Shirai
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Claire Steppan
4Worldwide Research and Development, Pfizer Inc., Groton, CT 06340
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Martyn Ticehurst
7Worldwide Research and Development, Pfizer Inc., Sandwich, CT13 9ND, UK
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Lawrence W. Updyke
3Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139
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Stuart Weston
14Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD 21201
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Yuao Zhu
2Worldwide Research and Development, Pfizer Inc., Pearl River, NY 10965
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Jun Wang
8Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721
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Arnab K. Chatterjee
11Calibr, a division of The Scripps Research Institute, La Jolla, CA 92037
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  • ORCID record for Arnab K. Chatterjee
Andrew D. Mesecar
9Department of Biological Sciences, Purdue University, West Lafayette, IN, 47907 USA
10Department of Biochemistry, Purdue University, West Lafayette, IN, 47907 USA
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Matthew B. Frieman
14Department of Microbiology and Immunology University of Maryland School of Medicine, Baltimore, MD 21201
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Annaliesa S. Anderson
2Worldwide Research and Development, Pfizer Inc., Pearl River, NY 10965
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Charlotte Allerton
3Worldwide Research and Development, Pfizer Inc., Cambridge, MA 02139
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  • Abstract
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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. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro, and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.

Competing Interest Statement

A.D.M has a sponsored program contract with Pfizer to test compounds for inhibition of coronavirus proteases. JW has a sponsored research agreement with Pfizer to test compounds for inhibition of coronavirus proteases. The Frieman Laboratory was funded by Pfizer for the work in this manuscript.

Footnotes

  • One Sentence Summary: PF-07304814, a novel phosphate prodrug is disclosed as an investigational novel intravenous small molecule 3CL protease inhibitor for the potential treatment of COVID-19 and other coronavirus infections.

  • One small typo in the abstract. The compound ID number should be PF-00835231 and in the abstract the number is PF-00835321 in one place. This has been corrected in the abstract and in the manuscript. Version 3: Added in vivo efficacy data, section Activity of PF-00835231 in a mouse model of SARS-CoV-1 infection and Figure 4.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 12, 2021.
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Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19
Britton Boras, Rhys M. Jones, Brandon J. Anson, Dan Arenson, Lisa Aschenbrenner, Malina A. Bakowski, Nathan Beutler, Joseph Binder, Emily Chen, Heather Eng, Holly Hammond, Jennifer Hammond, Robert E. Haupt, Robert Hoffman, Eugene P. Kadar, Rob Kania, Emi Kimoto, Melanie G. Kirkpatrick, Lorraine Lanyon, Emma K. Lendy, Jonathan R. Lillis, James Logue, Suman A. Luthra, Chunlong Ma, Stephen W. Mason, Marisa E. McGrath, Stephen Noell, R. Scott Obach, Matthew N. O’Brien, Rebecca O’Connor, Kevin Ogilvie, Dafydd Owen, Martin Pettersson, Matthew R Reese, Thomas F. Rogers, Michelle I. Rossulek, Jean G. Sathish, Norimitsu Shirai, Claire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Stuart Weston, Yuao Zhu, Jun Wang, Arnab K. Chatterjee, Andrew D. Mesecar, Matthew B. Frieman, Annaliesa S. Anderson, Charlotte Allerton
bioRxiv 2020.09.12.293498; doi: https://doi.org/10.1101/2020.09.12.293498
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Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19
Britton Boras, Rhys M. Jones, Brandon J. Anson, Dan Arenson, Lisa Aschenbrenner, Malina A. Bakowski, Nathan Beutler, Joseph Binder, Emily Chen, Heather Eng, Holly Hammond, Jennifer Hammond, Robert E. Haupt, Robert Hoffman, Eugene P. Kadar, Rob Kania, Emi Kimoto, Melanie G. Kirkpatrick, Lorraine Lanyon, Emma K. Lendy, Jonathan R. Lillis, James Logue, Suman A. Luthra, Chunlong Ma, Stephen W. Mason, Marisa E. McGrath, Stephen Noell, R. Scott Obach, Matthew N. O’Brien, Rebecca O’Connor, Kevin Ogilvie, Dafydd Owen, Martin Pettersson, Matthew R Reese, Thomas F. Rogers, Michelle I. Rossulek, Jean G. Sathish, Norimitsu Shirai, Claire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Stuart Weston, Yuao Zhu, Jun Wang, Arnab K. Chatterjee, Andrew D. Mesecar, Matthew B. Frieman, Annaliesa S. Anderson, Charlotte Allerton
bioRxiv 2020.09.12.293498; doi: https://doi.org/10.1101/2020.09.12.293498

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