7QUW

From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease.

(2022) Molecules 27

• PubMed: 35807537 Search on PubMedSearch on PubMed Central
• DOI: https://doi.org/10.3390/molecules27134292
• Primary Citation of Related Structures:  
  7QL8, 7QUB, 7QUW, 7Z0P


• PubMed Abstract: 
  

  The main protease (M ^pro ) of the betacoronavirus SARS-CoV-2 is an attractive target for the development of treatments for COVID-19. Structure-based design is a successful approach to discovering new inhibitors of the M ^pro . Starting from crystal structures of the M ^pro in complexes with the Hepatitis C virus NS3/4A protease inhibitors boceprevir and telaprevir, we optimized the potency of the alpha-ketoamide boceprevir against the M ^pro by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, MG-78 , exhibited an IC ₅₀ of 13 nM versus the recombinant M ^pro , and similar potency was observed for its P1' N -methyl derivative MG-131 . Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 M ^pro inhibition, we also explored the activity of MG-78 against the M ^pro of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 M ^pro ), moderate (1.45 µM, Coxsackievirus 3C ^pro ), and relatively poor (6.7 µM, enterovirus A71 3C ^pro ), respectively. The structural basis for the differences in activities was revealed by X-ray crystallo-graphy. We conclude that the modified boceprevir scaffold is suitable for obtaining high-potency inhibitors of the coronavirus M ^pro s but further optimization would be needed to target enterovirus 3C ^pro s efficiently.

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Organizational Affiliation: 

Department of Chemical Biology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.