Authors
Yugendar R Alugubelli, Veerabhadra R Vulupala, Kai S Yang, Kaustav Khatua, Lauren R Blankenship, Sathish Kumar, Demonta Coleman, Xuejiao Guo, Zhi Zachery Geng, Chia-Chuan D Cho, Banumathi Sankaran, Benjamin W Neuman, Shiqing Xu, Wenshe Ray Liu
Published in
ChemMedChem. Volume 21. Issue 15. Pages e70424. Aug 14, 2026.
Abstract
Nirmatrelvir (NMV) is a SARS-CoV-2 antiviral component of the approved COVID-19 therapeutic Paxlovid. It is a reversible covalent inhibitor of SARS-CoV-2 main protease (MPro) that is effluxed from human cells by P-glycoprotein (P-gp). To identify NMV analogs with improved potency and reduced P-gp efflux, a structure-activity relationship campaign was conducted. Warheads alternative to nitrile for engaging the active site cysteine were tested showing aldehyde and dichloroacetamide with better enzyme inhibition potency. Crystal structure of MPI-136-MPro shows its aldehyde warhead forming a thiohemiacetal with active Cys145 of MPro. Several S4 binders were explored revealing that an O-to-S shift at the N-terminal amide leads to better enzyme inhibition. By exploring different combinations of S2, S3, and S4 binders, two inhibitors with better enzyme inhibition potency than NMV were found. Crystal structure of MPI-148, with (S)-2-azaspiro[4,5]decane-3-carboxylate as an alternative S2 binder, shows extensive hydrogen-bond networks for locking the inhibitor in active site, explaining high affinity of NMV analogs. Further characterization of cellular MPro engagement and antiviral potency against SARS-CoV-2 revealed four inhibitors with greater potency than NMV in P-gp-expressing cells. Studies with the P-gp inhibitor CP-100356 showed that these compounds were less sensitive to P-gp inhibition than NMV, consistent with reduced P-gp-mediated efflux.
PMID:
42580866
Bibliographic data and abstract were imported from PubMed on 12 Aug 2026.
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