Boroleucine‐Derived Covalent Inhibitors of the ZIKV Protease

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 K (i) 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.