Publication
Article Metrics
Citations
Online attention
More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules
DOI:
10.1038/nsmb.2769
PMID:
24509833
Authors:
Luigi
De Colibus
(University of Oxford)
,
Xiangxi
Wang
(Institute of Biophysics, Chinese Academy of Science,)
,
John A. B.
Spyrou
(University of Oxford)
,
James
Kelly
(University of Leeds)
,
Jingshan
Ren
(University of Oxford)
,
Jonathan
Grimes
(University of Oxford)
,
Gerhard
Puerstinger
(University of Innsbruck)
,
Nicola
Stonehouse
(University of Leeds)
,
Thomas
Walter
(University of Oxford)
,
Zhongyu
Hu
(National Institutes for Food and Drug Control (China))
,
Junzhi
Wang
(National Institutes for Food and Drug Control (China))
,
Xuemei
Li
(Institute of Biophysics, Chinese Academy of Science)
,
Wei
Peng
(Institute of Biophysics, Chinese Academy of Science)
,
David J.
Rowlands
(University of Leeds)
,
Elizabeth E.
Fry
(University of Oxford)
,
Zihe
Rao
(Institute of Biophysics, Chinese Academy of Science; Tsinghua University)
,
David I.
Stuart
(University of Oxford; Diamond Light Source)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Nature Structural & Molecular Biology
, VOL 21 (3)
, PAGES 282 - 288
State:
Published (Approved)
Published:
February 2014
Diamond Proposal Number(s):
8423
Abstract: Enterovirus 71 (HEV71) epidemics in children and infants result mainly in mild symptoms; however, especially in the Asia-Pacific region, infection can be fatal. At present, no therapies are available. We have used structural analysis of the complete virus to guide the design of HEV71 inhibitors. Analysis of complexes with four 3-(4-pyridyl)-2-imidazolidinone derivatives with varying anti-HEV71 activities pinpointed key structure-activity correlates. We then identified additional potentially beneficial substitutions, developed methods to reliably triage compounds by quantum mechanics enhanced ligand docking and synthesized two candidates. Structural analysis and in vitro assays confirmed the predicted binding modes and their ability to block viral infection. One ligand (with IC50 of 25 pM) is an order of magnitude more potent than the best previously reported inhibitor and is also more soluble. Our approach may be useful in the design of effective drugs for enterovirus infections.
Journal Keywords: Binding; Capsid; Capsid; Chemistry; Pharmaceutical; Drug; Enterovirus; Human; Enterovirus; Imidazoles; Inhibitory; Ligands; Protein; Structure-Activity Relationship
Diamond Keywords: Enterovirus 71; Viruses
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I03-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography
Added On:
26/03/2014 19:01
Discipline Tags:
Pathogens
Infectious Diseases
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)