Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0180632
Title: Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants
Authors: Roy A. 
Lim L. 
Srivastava S.
Lu Y. 
Song J. 
Keywords: apigenin
aprotinin
catechin
curcumin
daidzein
flavonoid
isorhamnetin
luteolin
myricetin
natural product
NS2B NS3 protease
phenol
proteinase
quercetin
resveratrol
serine proteinase inhibitor
unclassified drug
biological product
buffer
NS2B protein, flavivirus
NS3 protein, flavivirus
RNA helicase
serine proteinase
solution and solubility
viral protein
Article
carboxy terminal sequence
catalysis
circular dichroism
drug identification
enzyme activity
enzyme conformation
enzyme inhibition
enzyme kinetics
fruit
IC50
molecular cloning
molecular docking
nonhuman
nuclear magnetic resonance spectroscopy
plasmid
protein expression
protein purification
protein secondary structure
protein tertiary structure
structure activity relation
vegetable
Zika virus
antagonists and inhibitors
binding site
biocatalysis
biophysics
chemistry
drug effects
edible plant
hydrogen bond
isolation and purification
kinetics
metabolism
molecular model
protein conformation
solution and solubility
Zika virus
Binding Sites
Biocatalysis
Biological Products
Biophysical Phenomena
Buffers
Cloning, Molecular
Hydrogen Bonding
Kinetics
Models, Molecular
Plants, Edible
Protein Conformation
RNA Helicases
Serine Endopeptidases
Solutions
Viral Nonstructural Proteins
Zika Virus
Issue Date: 2017
Publisher: Public Library of Science
Citation: Roy A., Lim L., Srivastava S., Lu Y., Song J. (2017). Solution conformations of Zika NS2B-NS3pro and its inhibition by natural products from edible plants. PLoS ONE 12 (7) : e0180632. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0180632
Abstract: The recent Zika viral (ZIKV) epidemic has been associated with severe neurological pathologies such as neonatal microcephaly and Guillain-Barre syndrome but unfortunately no vaccine or medication is effectively available yet. Zika NS2B-NS3pro is essential for the pro-teolysis of the viral polyprotein and thereby viral replication. Thus NS2B-NS3pro represents an attractive target for anti-Zika drug discovery/design. Here, we have characterized the solution conformations and catalytic parameters of both linked and unlinked Zika NS2B-NS3pro complexes and found that the unlinked complex manifested well-dispersed NMR spectra. Subsequently with selective isotope-labeling using NMR spectroscopy, we demonstrated that C-terminal residues (R73-K100) of NS2B is highly disordered without any stable tertiary and secondary structures in the Zika NS2B-NS3pro complex in the free state. Upon binding to the well-characterized serine protease inhibitor, bovine pancreatic trypsin inhibitor (BPTI), only the extreme C-terminal residues (L86-K100) remain disordered. Additionally, we have identified five flavonoids and one natural phenol rich in edible plants including fruits and vegetables, which inhibit Zika NS2B-NS3pro in a non-competitive mode, with Ki ranging from 770 nM for Myricetin to 34.02 ?M for Apigenin. Molecular docking showed that they all bind to a pocket on the back of the active site and their structure-activity relationship was elucidated. Our study provides valuable insights into the solution conformation of Zika NS2B-NS3pro and further deciphers its susceptibility towards allosteric inhibition by natural products. As these natural product inhibitors fundamentally differ from the currently-known active site inhibitors in terms of both inhibitory mode and chemical scaffold, our finding might open a new avenue for development of better allosteric inhibitors to fight ZIKV infection. © 2017 Roy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/165787
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0180632
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