8H3L

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) Double Mutant (T21I and E166V) in Complex with Inhibitor Enstrelvir

Summary for 8H3L

• Entry DOI: 10.2210/pdb8h3l/pdb
• Descriptor: 3C-like proteinase nsp5, 6-[(6-chloranyl-2-methyl-indazol-5-yl)amino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[[2,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazine-2,4-dione (3 entities in total)
• Functional Keywords: sars-cov-2, mutant, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 4
• Total formula weight: 137357.98

Authors

Wang, H.,Lin, M.,Duan, Y.,Zhang, X.,Zhou, H.,Bian, Q.,Liu, X.,Rao, Z.,Yang, H. (deposition date: 2022-10-08, release date: 2023-10-11, Last modification date: 2023-10-25)

Primary citation

Duan, Y.,Zhou, H.,Liu, X.,Iketani, S.,Lin, M.,Zhang, X.,Bian, Q.,Wang, H.,Sun, H.,Hong, S.J.,Culbertson, B.,Mohri, H.,Luck, M.I.,Zhu, Y.,Liu, X.,Lu, Y.,Yang, X.,Yang, K.,Sabo, Y.,Chavez, A.,Goff, S.P.,Rao, Z.,Ho, D.D.,Yang, H.
Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir.
Nature, 622:376-382, 2023

PubMed Abstract: Nirmatrelvir is a specific antiviral drug that targets the main protease (M) of SARS-CoV-2 and has been approved to treat COVID-19. As an RNA virus characterized by high mutation rates, whether SARS-CoV-2 will develop resistance to nirmatrelvir is a question of concern. Our previous studies have shown that several mutational pathways confer resistance to nirmatrelvir, but some result in a loss of viral replicative fitness, which is then compensated for by additional alterations. The molecular mechanisms for this observed resistance are unknown. Here we combined biochemical and structural methods to demonstrate that alterations at the substrate-binding pocket of M can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of the structures of 14 M mutants in complex with drugs or substrate revealed that alterations at the S1 and S4 subsites substantially decreased the level of inhibitor binding, whereas alterations at the S2 and S4' subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, with the latter compensating for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness, as observed previously. Such a profile was also observed for ensitrelvir, another clinically relevant M inhibitor. These results shed light on the mechanisms by which SARS-CoV-2 evolves to develop resistance to the current generation of protease inhibitors and provide the basis for the design of next-generation M inhibitors.

PubMed: 37696289
DOI: 10.1038/s41586-023-06609-0

Experimental method

X-RAY DIFFRACTION (2.3 Å)