Allosteric Inhibitors of Zika Virus NS2B-NS3 Protease Targeting Protease in "Super-Open" Conformation

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...

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Bibliographic Details
Published in:Viruses 2023-04, Vol.15 (5), p.1106
Main Authors: Meewan, Ittipat, Shiryaev, Sergey A, Kattoula, Julius, Huang, Chun-Teng, Lin, Vivian, Chuang, Chiao-Han, Terskikh, Alexey V, Abagyan, Ruben
Format: Article
Language:English
Subjects:
Allosteric enzymes
allosteric inhibitors
Allosteric properties
Conformation
Crystal structure
Drug development
Glycerol
Guillain-Barre syndrome
Health aspects
Humans
Hydrophobicity
Infant, Newborn
Infections
Medical research
Medicine, Experimental
Microcephaly
Microencephaly
Neonates
Peptide Hydrolases
Peptides
Pharmacology, Experimental
Physiological aspects
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Proteases
Protein Conformation
Proteins
Proteolysis
Serine Endopeptidases - metabolism
super-open conformation
Viral Nonstructural Proteins - chemistry
Zika virus
Zika Virus - metabolism
Zika Virus Infection - drug therapy
Zika virus NS2B-NS3 protease
Zika virus protease inhibitors
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Summary: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.
ISSN:1999-4915
1999-4915
DOI:10.3390/v15051106