Boroleucine-Derived Covalent Inhibitors of the ZIKV Protease

ChemMedChem. 2022 Nov 3;e202200336. doi: 10.1002/cmdc.202200336. Online ahead of print.


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.

Keywords: NS2B-NS3 protease; Zika virus; boroleucine; crystal structure determination; drug design.