1. Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in “Super-Open” Conformation
- Author
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Meewan, Ittipat, Shiryaev, Sergey A, Kattoula, Julius, Huang, Chun-Teng, Lin, Vivian, Chuang, Chiao-Han, Terskikh, Alexey V, and Abagyan, Ruben
- Subjects
Microbiology ,Biological Sciences ,Vector-Borne Diseases ,Orphan Drug ,Rare Diseases ,Infectious Diseases ,Biodefense ,Emerging Infectious Diseases ,5.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Infant ,Newborn ,Humans ,Zika Virus ,Zika Virus Infection ,Viral Nonstructural Proteins ,Serine Endopeptidases ,Peptide Hydrolases ,Protein Conformation ,Protease Inhibitors ,Zika virus protease inhibitors ,allosteric inhibitors ,Zika virus NS2B-NS3 protease ,super-open conformation - Abstract
The Zika virus (ZIKV), a member of the Flaviviridae family, is considered a major health threat causing multiple cases of microcephaly in newborns and Guillain-Barré syndrome in adults. In this study, we targeted a transient, deep, and hydrophobic pocket of the "super-open" conformation of ZIKV NS2B-NS3 protease to overcome the limitations of the active site pocket. After virtual docking screening of approximately seven million compounds against the novel allosteric site, we selected the top six candidates and assessed them in enzymatic assays. Six candidates inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations. These six compounds, targeting the selected protease pocket conserved in ZIKV, serve as unique drug candidates and open new opportunities for possible treatment against several flavivirus infections.
- Published
- 2023