tetano
Editor, Senior Moderator
Nat Commun
. 2025 May 16;16(1):4548.
doi: 10.1038/s41467-025-59922-9. Identification of naturally occurring drug-resistant mutations of SARS-CoV-2 papain-like protease
Haozhou Tan[SUP] #[/SUP][SUP] 1 [/SUP], Qianru Zhang[SUP] #[/SUP][SUP] 2 [/SUP], Kyriakos Georgiou[SUP] 3 [/SUP], Siyu Zhang[SUP] 2 [/SUP], Kan Li[SUP] 1 [/SUP], George Lambrinidis[SUP] 3 [/SUP], Antonios Kolocouris[SUP] 3 [/SUP], Xufang Deng[SUP] 4 5 [/SUP], Jun Wang[SUP] 6 [/SUP]
Affiliations
The SARS-CoV-2 papain-like protease (PL[SUP]pro[/SUP]) 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 PL[SUP]pro[/SUP] 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 PL[SUP]pro[/SUP] mutants showing significant drug resistance while maintaining comparable enzymatic activity as the wild-type PL[SUP]pro[/SUP]. 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 PL[SUP]pro[/SUP] mutants weaken hydrogen bonding and π-π stacking interactions. Collectively, this study identifies E167, Y268, and Q269 as drug-resistant hotspots for PL[SUP]pro[/SUP] inhibitors that bind to the BL2 loop and groove region, which are valuable in informing the design of the next-generation PL[SUP]pro[/SUP] inhibitors.
. 2025 May 16;16(1):4548.
doi: 10.1038/s41467-025-59922-9. Identification of naturally occurring drug-resistant mutations of SARS-CoV-2 papain-like protease
Haozhou Tan[SUP] #[/SUP][SUP] 1 [/SUP], Qianru Zhang[SUP] #[/SUP][SUP] 2 [/SUP], Kyriakos Georgiou[SUP] 3 [/SUP], Siyu Zhang[SUP] 2 [/SUP], Kan Li[SUP] 1 [/SUP], George Lambrinidis[SUP] 3 [/SUP], Antonios Kolocouris[SUP] 3 [/SUP], Xufang Deng[SUP] 4 5 [/SUP], Jun Wang[SUP] 6 [/SUP]
Affiliations
- PMID: 40379662
- PMCID: PMC12084387
- DOI: 10.1038/s41467-025-59922-9
The SARS-CoV-2 papain-like protease (PL[SUP]pro[/SUP]) 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 PL[SUP]pro[/SUP] 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 PL[SUP]pro[/SUP] mutants showing significant drug resistance while maintaining comparable enzymatic activity as the wild-type PL[SUP]pro[/SUP]. 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 PL[SUP]pro[/SUP] mutants weaken hydrogen bonding and π-π stacking interactions. Collectively, this study identifies E167, Y268, and Q269 as drug-resistant hotspots for PL[SUP]pro[/SUP] inhibitors that bind to the BL2 loop and groove region, which are valuable in informing the design of the next-generation PL[SUP]pro[/SUP] inhibitors.