Structural Basis for the Inhibition of SARS-CoV-2 M[sup.pro] D48N Mutant by Shikonin and PF-07321332

• Published in: Viruses 2023-12, Vol.16 (1)
• Main Authors: Zhenyu Zhao, Qinyao Zhu, Xuelan Zhou, Wenwen Li, Xiushan Yin, Jian Li
• Format: Article
• Language: English
• Subjects: Physiological aspects; Proteases
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v16010065

Preventing the spread of SARS-CoV-2 and its variants is crucial in the fight against COVID-19. Inhibition of the main protease (M[sup.pro] ) of SARS-CoV-2 is the key to disrupting viral replication, making M[sup.pro] a promising target for therapy. PF-07321332 and shikonin have been identified as effective broad-spectrum inhibitors of SARS-CoV-2 M[sup.pro] . The crystal structures of SARS-CoV-2 M[sup.pro] bound to PF-07321332 and shikonin have been resolved in previous studies. However, the exact mechanism regarding how SARS-CoV-2 M[sup.pro] mutants impact their binding modes largely remains to be investigated. In this study, we expressed a SARS-CoV-2 M[sup.pro] mutant, carrying the D48N substitution, representing a class of mutations located near the active sites of M[sup.pro] . The crystal structures of M[sup.pro] D48N in complex with PF-07321332 and shikonin were solved. A detailed analysis of the interactions between M[sup.pro] D48N and two inhibitors provides key insights into the binding pattern and its structural determinants. Further, the binding patterns of the two inhibitors to M[sup.pro] D48N mutant and wild-type M[sup.pro] were compared in detail. This study illustrates the possible conformational changes when the M[sup.pro] D48N mutant is bound to inhibitors. Structural insights derived from this study will inform the development of new drugs against novel coronaviruses.