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Publication Abstract from PubMed

Zika virus (ZIKV) has been a serious public health problem, and there is no vaccine or drug approved for the prevention or treatment of ZIKV yet. The ZIKV NS2B/NS3 protease plays an important role in processing the virus precursor polyprotein and is thus a promising target for antiviral drugs development. In order to discover novel inhibitors of this protease, we carried out a fragment-based hit screening and characterized protein-inhibitor interactions using the X-ray crystallography together with isothermal titration calorimetry. We reported two high-resolution crystal structures of the protease (bZiPro(C143S)) in complex with an active fragment as well as a tetrapeptide, revealing that there is domain swapping in the protein structures and two ligands only occupy the substrate-binding pocket of one copy in a symmetric unit. Based on the detailed binding modes of two ligands revealed by crystal structures, we designed a novel inhibitor which inhibits the NS2B/NS3 protease with a higher potency than the fragment and possesses a higher ligand-binding efficiency and a comparable IC50 compared to the tetrapeptide. These results thus provide a structural basis and valuable hint for development of more potent inhibitors of the ZIKV NS2B/NS3 protease.

Structure-based design of a novel inhibitor of the ZIKA virus NS2B/NS3 protease.,Xiong Y, Cheng F, Zhang J, Su H, Hu H, Zou Y, Li M, Xu Y Bioorg Chem. 2022 Nov;128:106109. doi: 10.1016/j.bioorg.2022.106109. Epub 2022, Aug 25. PMID:36049322^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.