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The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo

Author

Listed:
  • Michael H. J. Rhodin

    (Inc.)

  • Archie C. Reyes

    (Inc.)

  • Anand Balakrishnan

    (Inc.)

  • Nalini Bisht

    (Inc.)

  • Nicole M. Kelly

    (Inc.)

  • Joyce Sweeney Gibbons

    (Inc.)

  • Jonathan Lloyd

    (Inc.)

  • Michael Vaine

    (Inc.)

  • Tessa Cressey

    (Inc.)

  • Miranda Crepeau

    (Inc.)

  • Ruichao Shen

    (Inc.)

  • Nathan Manalo

    (Inc.)

  • Jonathan Castillo

    (Inc.)

  • Rachel E. Levene

    (Inc.)

  • Daniel Leonard

    (Inc.)

  • Tianzhu Zang

    (Inc.)

  • Lijuan Jiang

    (Inc.)

  • Kellye Daniels

    (Inc.)

  • Robert M. Cox

    (Georgia State University)

  • Carolin M. Lieber

    (Georgia State University)

  • Josef D. Wolf

    (Georgia State University)

  • Richard K. Plemper

    (Georgia State University)

  • Sarah R. Leist

    (University of North Carolina at Chapel Hill)

  • Trevor Scobey

    (University of North Carolina at Chapel Hill)

  • Ralph S. Baric

    (University of North Carolina at Chapel Hill)

  • Guoqiang Wang

    (Inc.)

  • Bryan Goodwin

    (Inc.)

  • Yat Sun Or

    (Inc.)

Abstract

The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

Suggested Citation

  • Michael H. J. Rhodin & Archie C. Reyes & Anand Balakrishnan & Nalini Bisht & Nicole M. Kelly & Joyce Sweeney Gibbons & Jonathan Lloyd & Michael Vaine & Tessa Cressey & Miranda Crepeau & Ruichao Shen &, 2024. "The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50931-8
    DOI: 10.1038/s41467-024-50931-8
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