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

Author

Listed:
  • Britton Boras

    (Worldwide Research and Development, Pfizer Inc)

  • Rhys M. Jones

    (Worldwide Research and Development, Pfizer Inc)

  • Brandon J. Anson

    (Purdue University)

  • Dan Arenson

    (Worldwide Research and Development, Pfizer Inc)

  • Lisa Aschenbrenner

    (Worldwide Research and Development, Pfizer Inc)

  • Malina A. Bakowski

    (Calibr, a division of The Scripps Research Institute)

  • Nathan Beutler

    (The Scripps Research Institute)

  • Joseph Binder

    (Worldwide Research and Development, Pfizer Inc)

  • Emily Chen

    (Calibr, a division of The Scripps Research Institute)

  • Heather Eng

    (Worldwide Research and Development, Pfizer Inc)

  • Holly Hammond

    (Department of Microbiology and Immunology University of Maryland School of Medicine)

  • Jennifer Hammond

    (Worldwide Research and Development, Pfizer Inc.)

  • Robert E. Haupt

    (Department of Microbiology and Immunology University of Maryland School of Medicine)

  • Robert Hoffman

    (Worldwide Research and Development, Pfizer Inc)

  • Eugene P. Kadar

    (Worldwide Research and Development, Pfizer Inc)

  • Rob Kania

    (Worldwide Research and Development, Pfizer Inc)

  • Emi Kimoto

    (Worldwide Research and Development, Pfizer Inc)

  • Melanie G. Kirkpatrick

    (Calibr, a division of The Scripps Research Institute)

  • Lorraine Lanyon

    (Worldwide Research and Development, Pfizer Inc)

  • Emma K. Lendy

    (Purdue University)

  • Jonathan R. Lillis

    (Worldwide Research and Development, Pfizer Inc)

  • James Logue

    (Department of Microbiology and Immunology University of Maryland School of Medicine)

  • Suman A. Luthra

    (Worldwide Research and Development, Pfizer Inc)

  • Chunlong Ma

    (University of Arizona)

  • Stephen W. Mason

    (Worldwide Research and Development, Pfizer Inc
    Worldwide Research and Development, Pfizer Inc.)

  • Marisa E. McGrath

    (Department of Microbiology and Immunology University of Maryland School of Medicine)

  • Stephen Noell

    (Worldwide Research and Development, Pfizer Inc)

  • R. Scott Obach

    (Worldwide Research and Development, Pfizer Inc)

  • Matthew N. O’ Brien

    (Worldwide Research and Development, Pfizer Inc)

  • Rebecca O’Connor

    (Worldwide Research and Development, Pfizer Inc)

  • Kevin Ogilvie

    (Worldwide Research and Development, Pfizer Inc)

  • Dafydd Owen

    (Worldwide Research and Development, Pfizer Inc)

  • Martin Pettersson

    (Worldwide Research and Development, Pfizer Inc)

  • Matthew R. Reese

    (Worldwide Research and Development, Pfizer Inc)

  • Thomas F. Rogers

    (The Scripps Research Institute
    UC San Diego School of Medicine)

  • Romel Rosales

    (Icahn School of Medicine at Mount Sinai
    Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai)

  • Michelle I. Rossulek

    (Worldwide Research and Development, Pfizer Inc)

  • Jean G. Sathish

    (Worldwide Research and Development, Pfizer Inc.)

  • Norimitsu Shirai

    (Worldwide Research and Development, Pfizer Inc)

  • Claire Steppan

    (Worldwide Research and Development, Pfizer Inc)

  • Martyn Ticehurst

    (Worldwide Research and Development, Pfizer Inc)

  • Lawrence W. Updyke

    (Worldwide Research and Development, Pfizer Inc)

  • Stuart Weston

    (Department of Microbiology and Immunology University of Maryland School of Medicine)

  • Yuao Zhu

    (Worldwide Research and Development, Pfizer Inc.)

  • Kris M. White

    (Icahn School of Medicine at Mount Sinai
    Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai)

  • Adolfo García-Sastre

    (Icahn School of Medicine at Mount Sinai
    Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai)

  • Jun Wang

    (University of Arizona)

  • Arnab K. Chatterjee

    (Calibr, a division of The Scripps Research Institute)

  • Andrew D. Mesecar

    (Purdue University
    Purdue University)

  • Matthew B. Frieman

    (Department of Microbiology and Immunology University of Maryland School of Medicine)

  • Annaliesa S. Anderson

    (Worldwide Research and Development, Pfizer Inc.)

  • Charlotte Allerton

    (Worldwide Research and Development, Pfizer Inc)

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.

Suggested Citation

  • 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 , 2021. "Preclinical characterization of an intravenous coronavirus 3CL protease inhibitor for the potential treatment of COVID19," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26239-2
    DOI: 10.1038/s41467-021-26239-2
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    References listed on IDEAS

    as
    1. Peng Zhou & Xing-Lou Yang & Xian-Guang Wang & Ben Hu & Lei Zhang & Wei Zhang & Hao-Rui Si & Yan Zhu & Bei Li & Chao-Lin Huang & Hui-Dong Chen & Jing Chen & Yun Luo & Hua Guo & Ren-Di Jiang & Mei-Qin L, 2020. "Addendum: A pneumonia outbreak associated with a new coronavirus of probable bat origin," Nature, Nature, vol. 588(7836), pages 6-6, December.
    2. Peng Zhou & Xing-Lou Yang & Xian-Guang Wang & Ben Hu & Lei Zhang & Wei Zhang & Hao-Rui Si & Yan Zhu & Bei Li & Chao-Lin Huang & Hui-Dong Chen & Jing Chen & Yun Luo & Hua Guo & Ren-Di Jiang & Mei-Qin L, 2020. "A pneumonia outbreak associated with a new coronavirus of probable bat origin," Nature, Nature, vol. 579(7798), pages 270-273, March.
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    Cited by:

    1. Maki Kiso & Seiya Yamayoshi & Shun Iida & Yuri Furusawa & Yuichiro Hirata & Ryuta Uraki & Masaki Imai & Tadaki Suzuki & Yoshihiro Kawaoka, 2023. "In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    2. Hengrui Liu & Sho Iketani & Arie Zask & Nisha Khanizeman & Eva Bednarova & Farhad Forouhar & Brandon Fowler & Seo Jung Hong & Hiroshi Mohri & Manoj S. Nair & Yaoxing Huang & Nicholas E. S. Tay & Sumin, 2022. "Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Daniel W. Kneller & Hui Li & Gwyndalyn Phillips & Kevin L. Weiss & Qiu Zhang & Mark A. Arnould & Colleen B. Jonsson & Surekha Surendranathan & Jyothi Parvathareddy & Matthew P. Blakeley & Leighton Coa, 2022. "Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Dongtak Lee & Hyo Gi Jung & Dongsung Park & Junho Bang & Da Yeon Cheong & Jae Won Jang & Yonghwan Kim & Seungmin Lee & Sang Won Lee & Gyudo Lee & Yeon Ho Kim & Ji Hye Hong & Kyo Seon Hwang & Jeong Hoo, 2024. "Bioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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