Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors

Bin Tan, Michael Sacco, Haozhou Tan, Kan Li, Ryan Joyce, Xiujun Zhang, Yu Chen, Jun Wang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


SARS-CoV-2 main protease (Mpro) is a validated antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant Mpro mutants against nirmatrelvir have been identified from cell culture viral passage and naturally occurring variants. As such, there is a need for a second generation of Mpro inhibitors. In this study, we explored several reactive warheads in the design of Mpro inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent Mpro inhibitors. Jun10541R and Jun10963R also had potent antiviral activity against SARS-CoV-2 in Calu-3 cells with EC50 values of 2.92 and 6.47 μM, respectively. X-ray crystal structures of Mpro with Jun10541R and Jun10221 revealed covalent modification of Cys145. These Mpro inhibitors with diverse reactive warheads collectively represent promising candidates for further development.

Original languageEnglish (US)
Article number115667
JournalEuropean journal of medicinal chemistry
StatePublished - Nov 5 2023
Externally publishedYes


  • 3CL protease
  • Antiviral
  • COVID-19
  • Main protease
  • SARS-CoV-2

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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