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Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity
- Source :
- Journal of Medicinal Chemistry; 20250101, Issue: Preprints
- Publication Year :
- 2025
-
Abstract
- The main protease (Mpro) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 Mproinhibitors, including compounds 8n(IC50= 0.0752 μM), 8p(IC50= 0.0887 μM), 8r(IC50= 0.0199 μM), 10a(IC50= 0.0376 μM), 10c(IC50= 0.0177 μM), and 10f(IC50= 0.0130 μM). Most of them additionally inhibited cathepsin L and were also active against SARS-CoV-1 and MERS-CoV Mpro. In Calu-3 cells, several inhibitors, including 8r, 10a, and 10c, displayed high antiviral activity in the nanomolar range without showing cellular toxicity. The cocrystal structure of SARS-CoV-2 Mproin complex with 8prevealed covalent binding to the enzyme’s catalytic residue Cys145 and showed specific, unprecedented interactions within the substrate binding pocket. Compounds 10cand especially 8nwere effective against a panel of naturally occurring nirmatrelvir-resistant mutants, particularly E166V, and showed metabolic stability and additional favorable pharmacokinetic properties, making it a suitable candidate for further preclinical development.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Issue :
- Preprints
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs68628948
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.4c02254