Development of the Safe and Broad-Spectrum Aldehyde and Ketoamide Mpro inhibitors Derived from the Constrained α, γ-AA Peptide Scaffold

Lei Wang, Chunlong Ma, Michael Dominic Sacco, Songyi Xue, Mentalla Mahmoud, Laurent Calcul, Yu Chen, Jun Wang, Jianfeng Cai

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

SARS-CoV-2 is still wreaking havoc all over the world with surging morbidity and high mortality. The main protease (Mpro) is essential in the replication of SARS-CoV-2, enabling itself an active target for antiviral development. Herein, we reported the design and synthesis of a new class of peptidomimetics-constrained α, γ-AA peptides, based on which a series of aldehyde and ketoamide inhibitors of the Mpro of SARS-CoV-2 were prepared. The lead compounds showed excellent inhibitory activity in the FRET-based Mpro enzymatic assay not only for the Mpro of SARS-CoV-2 but also for SARS-CoV and MERS-CoV, along with HCoVs like HCoV-OC43, HCoV-229E, HCoV-NL63 and HKU1. The X-ray crystallographic results demonstrated that our compounds form a covalent bond with the catalytic Cys145. They also demonstrated effective antiviral activity against live SARS-CoV-2. Overall, the results suggest that α, γ-AA peptide could be a promising molecular scaffold in designing novel Mpro inhibitors of SARS-CoV-2 and other coronaviruses.

Original languageEnglish (US)
Article numbere202300476
JournalChemistry - A European Journal
Volume29
Issue number35
DOIs
StatePublished - Jun 22 2023

Keywords

  • COVID-19
  • M inhibitor
  • SARS-CoV-2
  • X-ray structure
  • broad-spectrum activity

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Organic Chemistry

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