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Nat Commun
. 2024 Aug 1;15(1):6503.
doi: 10.1038/s41467-024-50931-8. The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo
Michael H J Rhodin 1 , Archie C Reyes 2 , Anand Balakrishnan 2 , Nalini Bisht 2 , Nicole M Kelly 2 , Joyce Sweeney Gibbons 2 , Jonathan Lloyd 2 , Michael Vaine 2 , Tessa Cressey 2 , Miranda Crepeau 2 , Ruichao Shen 2 , Nathan Manalo 2 , Jonathan Castillo 2 , Rachel E Levene 2 , Daniel Leonard 2 , Tianzhu Zang 2 , Lijuan Jiang 2 , Kellye Daniels 2 , Robert M Cox 3 , Carolin M Lieber 3 , Josef D Wolf 3 , Richard K Plemper 3 , Sarah R Leist 4 , Trevor Scobey 4 , Ralph S Baric 4 , Guoqiang Wang 2 , Bryan Goodwin 2 , Yat Sun Or 2
Affiliations
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.
. 2024 Aug 1;15(1):6503.
doi: 10.1038/s41467-024-50931-8. The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo
Michael H J Rhodin 1 , Archie C Reyes 2 , Anand Balakrishnan 2 , Nalini Bisht 2 , Nicole M Kelly 2 , Joyce Sweeney Gibbons 2 , Jonathan Lloyd 2 , Michael Vaine 2 , Tessa Cressey 2 , Miranda Crepeau 2 , Ruichao Shen 2 , Nathan Manalo 2 , Jonathan Castillo 2 , Rachel E Levene 2 , Daniel Leonard 2 , Tianzhu Zang 2 , Lijuan Jiang 2 , Kellye Daniels 2 , Robert M Cox 3 , Carolin M Lieber 3 , Josef D Wolf 3 , Richard K Plemper 3 , Sarah R Leist 4 , Trevor Scobey 4 , Ralph S Baric 4 , Guoqiang Wang 2 , Bryan Goodwin 2 , Yat Sun Or 2
Affiliations
- PMID: 39090095
- DOI: 10.1038/s41467-024-50931-8
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.