Year: 2026
Type: article
Abstract: MPI8 was among one of the first SARS-CoV-2 main protease (MPro) inhibitors with strong antiviral potency. Building on its peptidomimetic aldehyde scaffold, we retained the P2 3-cyclohexylalanine and P3 O-tert-butylthreonine elements, which support S2 binding, S-subsite engagement, and likely cellular permeability, and varied the S4/S1′ substituents and covalent warheads. SAR and co-crystal structures identified compact N-terminal carbamates or amides bearing cyclopropane, isopropyl, or trifluoromethyl groups as favorable S4 binders. Benzoxazole/benzothiazole-carbonyl groups and acyloxymethyl ketones were explored as S1′-engaging motifs, with one benzoxazole-containing structure confirming tight S1′ packing by crystal structure. Nitrile and 2-amino-2-oxyacetyl warheads provided viable alternatives to the parent aldehyde. Combining optimized S4 groups with alternative warheads or S1′ motifs yielded multiple inhibitors more potent than MPI8. Notably, MPI-131 showed an IC50 of 1.7 nM, strong antiviral potency, and CC50 of 60.2 μM, placing it among the most potent MPro inhibitors reported.
Source: Journal of Medicinal Chemistry
Authors: Veerabhadra R. Vulupala, Yugendar R. Alugubelli, Kaustav Khatua, Kai S. Yang, Xuejiao Shirley Guo, Dorsa Rabie, Tahmina Pervin, Lauren R. Blankenship, Demonta Coleman, Sathish Kumar, Chia-Chuan D. Cho, Zhi Zachary Geng, Xinyu R. Ma, Erol Vatansever, Banumathi Sankaran, Benjamin W. Neuman, Shiqing Xu, Wenshe Ray Liu
Institutions: Texas A&M University, Lawrence Berkeley National Laboratory
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: U.S. Department of Energy, Welch Foundation, Cancer Prevention and Research Institute of Texas, Texas A and M University, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Biomedical Imaging and Bioengineering
OpenAlex ID: W7225205285