Distal protein-protein interactions contribute to nirmatrelvir resistance

Eric M. Lewandowski, Xiujun Zhang, Haozhou Tan, Aiden Jaskolka-Brown, Navita Kohaal, Aliaksandra Frazier, Jesper J. Madsen, Lian M. C. Jacobs, Jun Wang () and Yu Chen ()
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Eric M. Lewandowski: University of South Florida
Xiujun Zhang: University of South Florida
Haozhou Tan: the State University of New Jersey
Aiden Jaskolka-Brown: University of South Florida
Navita Kohaal: University of South Florida
Aliaksandra Frazier: University of South Florida
Jesper J. Madsen: University of South Florida
Lian M. C. Jacobs: University of South Florida
Jun Wang: the State University of New Jersey
Yu Chen: University of South Florida

Nature Communications, 2025, vol. 16, issue 1, 1-8

Abstract: Abstract SARS-CoV-2 main protease, Mpro, is responsible for processing the viral polyproteins into individual proteins, including the protease itself. Mpro is a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component of Paxlovid). Resistance mutants identified clinically and in viral passage assays contain a combination of active site mutations (e.g., E166V, E166A, L167F), which reduce inhibitor binding and enzymatic activity, and non-active site mutations (e.g., P252L, T21I, L50F), which restore the fitness of viral replication. To probe the role of the non-active site mutations in fitness rescue, here we use an Mpro triple mutant (L50F/E166A/L167F) that confers nirmatrelvir drug resistance with a viral fitness level similar to the wild-type. By comparing peptide and full-length Mpro protein as substrates, we demonstrate that the binding of Mpro substrate involves more than residues in the active site. Particularly, L50F and other non-active site mutations can enhance the Mpro dimer-dimer interactions and help place the nsp5-6 substrate at the enzyme catalytic center. The structural and enzymatic activity data of Mpro L50F, L50F/E166A/L167F, and others underscore the importance of considering the whole substrate protein in studying Mpro and substrate interactions, and offers important insights into Mpro function, resistance development, and inhibitor design.

Date: 2025
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DOI: 10.1038/s41467-025-56651-x

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