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From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease
| Content Provider | MDPI |
|---|---|
| Author | Matthias, Göhl Mark, Brönstrup Zhang, Linlin Kilani, Haifa El Sun, Xinyuanyuan Zhang, Kaixuan Hilgenfeld, Rolf |
| Copyright Year | 2022 |
| Description | 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. |
| Starting Page | 4292 |
| e-ISSN | 14203049 |
| DOI | 10.3390/molecules27134292 |
| Journal | Molecules |
| Issue Number | 13 |
| Volume Number | 27 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2022-07-04 |
| Access Restriction | Open |
| Subject Keyword | Molecules Medicinal Chemistry Sars-cov-2 Covid-19 Main Protease 3c-like Protease Enterovirus 3c Protease Coxsackievirus B3 Structure-based Drug Design Alpha-ketoamides Boceprevir Telaprevir X-ray Crystallography |
| Content Type | Text |
| Resource Type | Article |
