Boroleucine-Derived Covalent Inhibitors of the ZIKV Protease |
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Authors: | Niklas J Braun Simon Huber Luna C Schmacke Prof Andreas Heine Prof Torsten Steinmetzer |
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Affiliation: | Institute of Pharmaceutical Chemistry, Philipps University of Marburg, Marbacher Weg 6, 35032 Marburg, Germany |
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Abstract: | The Zika virus (ZIKV) remains a potential threat to the public health due to the lack of both an approved vaccination or a specific treatment. In this work, a series of peptidic inhibitors of the ZIKV protease with boroleucine as P1 residue was synthesized. The highest affinities with Ki values down to 8 nM were observed for compounds with basic residues in both P2 and P3 position and at the N-terminus. The low potency of reference compounds containing leucine, leucine-amide or isopentylamide as P1 residue suggested a covalent binding mode of the boroleucine-derived inhibitors. This was finally proven by crystal structure determination of the most potent inhibitor from this series in complex with the ZIKV protease. |
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Keywords: | boroleucine crystal structure determination drug design NS2B-NS3 protease Zika virus |
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