Identification of naturally occurring drug-resistant mutations of SARS-CoV-2 papain-like protease
Haozhou Tan,
Qianru Zhang,
Kyriakos Georgiou,
Siyu Zhang,
Kan Li,
George Lambrinidis,
Antonios Kolocouris,
Xufang Deng () and
Jun Wang ()
Additional contact information
Haozhou Tan: Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey
Qianru Zhang: College of Veterinary Medicine, Oklahoma State University
Kyriakos Georgiou: National and Kapodistrian University of Athens
Siyu Zhang: College of Veterinary Medicine, Oklahoma State University
Kan Li: Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey
George Lambrinidis: National and Kapodistrian University of Athens
Antonios Kolocouris: National and Kapodistrian University of Athens
Xufang Deng: College of Veterinary Medicine, Oklahoma State University
Jun Wang: Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey
Nature Communications, 2025, vol. 16, issue 1, 1-18
Abstract:
Abstract The SARS-CoV-2 papain-like protease (PLpro) is a cysteine protease that cleaves viral polyproteins and antagonizes the host immune response during viral replication. Jun12682 and PF-07957472 are the first-in-class PLpro inhibitors showing potent in vivo antiviral efficacy in mouse models. In this study, we characterize naturally occurring mutations at residues located at the drug-binding site of Jun12682. The results reveal several PLpro mutants showing significant drug resistance while maintaining comparable enzymatic activity as the wild-type PLpro. The physiological relevance of the identified drug-resistant mutants, including E167G and Q269H, is validated through independent serial viral passage experiments. Molecular dynamics simulations and perturbative free energy calculations show that drug-resistant PLpro mutants weaken hydrogen bonding and π-π stacking interactions. Collectively, this study identifies E167, Y268, and Q269 as drug-resistant hotspots for PLpro inhibitors that bind to the BL2 loop and groove region, which are valuable in informing the design of the next-generation PLpro inhibitors.
Date: 2025
References: Add references at CitEc
Citations:
Downloads: (external link)
https://www.nature.com/articles/s41467-025-59922-9 Abstract (text/html)
Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.
Export reference: BibTeX
RIS (EndNote, ProCite, RefMan)
HTML/Text
Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59922-9
Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/
DOI: 10.1038/s41467-025-59922-9
Access Statistics for this article
Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie
More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().