IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26239-2.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26239-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26239-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Graziella Orrù & Ciro Conversano & Eleonora Malloggi & Francesca Francesconi & Rebecca Ciacchini & Angelo Gemignani, 2020. "Neurological Complications of COVID-19 and Possible Neuroinvasion Pathways: A Systematic Review," IJERPH, MDPI, vol. 17(18), pages 1-18, September.
    2. Susanne Kessler & Bradly Burke & Geoffroy Andrieux & Jan Schinköthe & Lea Hamberger & Johannes Kacza & Shijun Zhan & Clara Reasoner & Taru S. Dutt & Maria Kaukab Osman & Marcela Henao-Tamayo & Julian , 2024. "Deciphering bat influenza H18N11 infection dynamics in male Jamaican fruit bats on a single-cell level," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Yongzhu Xiong & Yunpeng Wang & Feng Chen & Mingyong Zhu, 2020. "Spatial Statistics and Influencing Factors of the COVID-19 Epidemic at Both Prefecture and County Levels in Hubei Province, China," IJERPH, MDPI, vol. 17(11), pages 1-26, May.
    4. Eugene Song & Jae-Eun Lee & Seola Kwon, 2021. "Effect of Public Empathy with Infection-Control Guidelines on Infection-Prevention Attitudes and Behaviors: Based on the Case of COVID-19," IJERPH, MDPI, vol. 18(24), pages 1-18, December.
    5. Jaeyong Lee & Calem Kenward & Liam J. Worrall & Marija Vuckovic & Francesco Gentile & Anh-Tien Ton & Myles Ng & Artem Cherkasov & Natalie C. J. Strynadka & Mark Paetzel, 2022. "X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Xu, Baochang & Li, Sihui & Afzal, Ayesha & Mirza, Nawazish & Zhang, Meng, 2022. "The impact of financial development on environmental sustainability: A European perspective," Resources Policy, Elsevier, vol. 78(C).
    7. Nur Hannani Bi Rahman & Shazmin Shareena A. Azis & Ibrahim Sipan, 2021. "COVID-19: Standard Operating Procedure Improvement For Green Office Building Using Indoor Environmental Quality," LARES lares-2021-4dqg, Latin American Real Estate Society (LARES).
    8. Eduardo Gutiérrez-Abejón & Eduardo Tamayo & Débora Martín-García & F. Javier Álvarez & Francisco Herrera-Gómez, 2020. "Clinical Profile, Treatment and Predictors during the First COVID-19 Wave: A Population-Based Registry Analysis from Castile and Leon Hospitals," IJERPH, MDPI, vol. 17(24), pages 1-15, December.
    9. Meriem Bekliz & Kenneth Adea & Pauline Vetter & Christiane S. Eberhardt & Krisztina Hosszu-Fellous & Diem-Lan Vu & Olha Puhach & Manel Essaidi-Laziosi & Sophie Waldvogel-Abramowski & Caroline Stephan , 2022. "Neutralization capacity of antibodies elicited through homologous or heterologous infection or vaccination against SARS-CoV-2 VOCs," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    10. Maria de Lourdes Aguiar-Oliveira & Aline Campos & Aline R. Matos & Caroline Rigotto & Adriana Sotero-Martins & Paulo F. P. Teixeira & Marilda M. Siqueira, 2020. "Wastewater-Based Epidemiology (WBE) and Viral Detection in Polluted Surface Water: A Valuable Tool for COVID-19 Surveillance—A Brief Review," IJERPH, MDPI, vol. 17(24), pages 1-19, December.
    11. Daiki Yamaguchi & Odgerel Chimed-Ochir & Yui Yumiya & Eisaku Kishita & Tomoyuki Akita & Junko Tanaka & Tatsuhiko Kubo, 2024. "Potential Risk Factors to COVID-19 Severity: Comparison of SARS-CoV-2 Delta- and Omicron-Dominant Periods," IJERPH, MDPI, vol. 21(3), pages 1-11, March.
    12. Dunbar, Kwamie, 2022. "Impact of the COVID-19 event on U.S. banks’ financial soundness," Research in International Business and Finance, Elsevier, vol. 59(C).
    13. Jian Rong & Ahmed Haider & Troels E. Jeppesen & Lee Josephson & Steven H. Liang, 2023. "Radiochemistry for positron emission tomography," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    14. Cecilia A. Sánchez & Hongying Li & Kendra L. Phelps & Carlos Zambrana-Torrelio & Lin-Fa Wang & Peng Zhou & Zheng-Li Shi & Kevin J. Olival & Peter Daszak, 2022. "A strategy to assess spillover risk of bat SARS-related coronaviruses in Southeast Asia," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    15. Sarwan Ali & Babatunde Bello & Murray Patterson, 2023. "Solvent Accessibility of Coronaviridae Spike Proteins through the Lens of Information Gain," J, MDPI, vol. 6(2), pages 1-12, April.
    16. Agata Jabłońska-Trypuć & Marcin Makuła & Maria Włodarczyk-Makuła & Elżbieta Wołejko & Urszula Wydro & Lluis Serra-Majem & Józefa Wiater, 2022. "Inanimate Surfaces as a Source of Hospital Infections Caused by Fungi, Bacteria and Viruses with Particular Emphasis on SARS-CoV-2," IJERPH, MDPI, vol. 19(13), pages 1-22, July.
    17. Yongin Choi & James Slghee Kim & Heejin Choi & Hyojung Lee & Chang Hyeong Lee, 2020. "Assessment of Social Distancing for Controlling COVID-19 in Korea: An Age-Structured Modeling Approach," IJERPH, MDPI, vol. 17(20), pages 1-16, October.
    18. Diego Fernández-Lázaro & Jerónimo J. González-Bernal & Nerea Sánchez-Serrano & Lourdes Jiménez Navascués & Ana Ascaso-del-Río & Juan Mielgo-Ayuso, 2020. "Physical Exercise as a Multimodal Tool for COVID-19: Could It Be Used as a Preventive Strategy?," IJERPH, MDPI, vol. 17(22), pages 1-13, November.
    19. Federico Alcide Villani & Riccardo Aiuto & Luigi Paglia & Dino Re, 2020. "COVID-19 and Dentistry: Prevention in Dental Practice, a Literature Review," IJERPH, MDPI, vol. 17(12), pages 1-12, June.
    20. Aishwarya Arjunan & Deanna R. Darnes & Katelynn G. Sagaser & Ashley B. Svenson, 2022. "Addressing Reproductive Healthcare Disparities through Equitable Carrier Screening: Medical Racism and Genetic Discrimination in United States’ History Highlights the Needs for Change in Obstetrical G," Societies, MDPI, vol. 12(2), pages 1-17, February.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26239-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.