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

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, Nathan Manalo, Jonathan Castillo, Rachel E. Levene, Daniel Leonard, Tianzhu Zang, Lijuan Jiang, Kellye Daniels, Robert M. Cox, Carolin M. Lieber, Josef D. Wolf, Richard K. Plemper, Sarah R. Leist, Trevor Scobey, Ralph S. Baric, Guoqiang Wang, Bryan Goodwin and Yat Sun Or
Additional contact information
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.

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50931-8

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