Summary for 7QUB
| Entry DOI | 10.2210/pdb7qub/pdb |
| Descriptor | Protease 3C, (1R,2S,5S)-N-{(2S,3R)-4-amino-3-hydroxy-4-oxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl}-3-[N-(tert-butylcarbamoyl)-3-methyl-L-valyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide, SODIUM ION, ... (4 entities in total) |
| Functional Keywords | inhibitor complex, sars-cov2, viral protein |
| Biological source | Human enterovirus 71 |
| Total number of polymer chains | 1 |
| Total formula weight | 20712.84 |
| Authors | El Kilani, H.,Hilgenfeld, R. (deposition date: 2022-01-17, release date: 2022-04-27, Last modification date: 2024-10-16) |
| Primary citation | Gohl, M.,Zhang, L.,El Kilani, H.,Sun, X.,Zhang, K.,Bronstrup, M.,Hilgenfeld, R. From Repurposing to Redesign: Optimization of Boceprevir to Highly Potent Inhibitors of the SARS-CoV-2 Main Protease. Molecules, 27:-, 2022 Cited by PubMed Abstract: The main protease (M) 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. Starting from crystal structures of the M 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 by replacing its P1 cyclobutyl moiety by a γ-lactam as a glutamine surrogate. The resulting compound, , exhibited an IC of 13 nM versus the recombinant M, and similar potency was observed for its P1' -methyl derivative . Crystal structures confirmed the validity of our design concept. In addition to SARS-CoV-2 M inhibition, we also explored the activity of against the M of the alphacoronavirus HCoV NL63 and against enterovirus 3C proteases. The activities were good (0.33 µM, HCoV-NL63 M), moderate (1.45 µM, Coxsackievirus 3C), and relatively poor (6.7 µM, enterovirus A71 3C), 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 Ms but further optimization would be needed to target enterovirus 3Cs efficiently. PubMed: 35807537DOI: 10.3390/molecules27134292 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.07 Å) |
Structure validation
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