8DKL

Polymorphism in SARS-CoV-2 Nsp5 main protease reveals differences in cleavage of viral and host substrates

Summary for 8DKL

• Entry DOI: 10.2210/pdb8dkl/pdb
• Descriptor: 3C-like proteinase nsp5 (2 entities in total)
• Functional Keywords: viral protein, hydrolase-hydrolase inhibitor complex, hydrolase, hydrolase-inhibitor complex
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 67719.12

Authors

Lu, J.,Khan, M.B.,Young, H.S.,Lemieux, M.J. (deposition date: 2022-07-05, release date: 2023-05-03, Last modification date: 2024-05-01)

Primary citation

Chen, S.A.,Arutyunova, E.,Lu, J.,Khan, M.B.,Rut, W.,Zmudzinski, M.,Shahbaz, S.,Iyyathurai, J.,Moussa, E.W.,Turner, Z.,Bai, B.,Lamer, T.,Nieman, J.A.,Vederas, J.C.,Julien, O.,Drag, M.,Elahi, S.,Young, H.S.,Lemieux, M.J.
SARS-CoV-2 M pro Protease Variants of Concern Display Altered Viral Substrate and Cell Host Target Galectin-8 Processing but Retain Sensitivity toward Antivirals.
Acs Cent.Sci., 9:696-708, 2023

PubMed Abstract: The main protease of SARS-CoV-2 (M) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there is a concern that mutations in M may alter the structural and functional properties of protease and subsequently the potency of existing and potential antivirals. We explored the effect of 31 mutations belonging to 5 variants of concern (VOCs) on catalytic parameters and substrate specificity, which revealed changes in substrate binding and the rate of cleavage of a viral peptide. Crystal structures of 11 M mutants provided structural insight into their altered functionality. Additionally, we show M mutations influence proteolysis of an immunomodulatory host protein Galectin-8 (Gal-8) and a subsequent significant decrease in cytokine secretion, providing evidence for alterations in the escape of host-antiviral mechanisms. Accordingly, mutations associated with the Gamma VOC and highly virulent Delta VOC resulted in a significant increase in Gal-8 cleavage. Importantly, IC50s of nirmatrelvir (Pfizer) and our irreversible inhibitor AVI-8053 demonstrated no changes in potency for both drugs for all mutants, suggesting M will remain a high-priority antiviral drug candidate as SARS-CoV-2 evolves.

PubMed: 37122453
DOI: 10.1021/acscentsci.3c00054

Experimental method

X-RAY DIFFRACTION (1.9 Å)