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More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules

DOI: 10.1038/nsmb.2769 DOI Help
PMID: 24509833 PMID Help

Authors: Luigi De Colibus (University of Oxford) , Xiangxi Wang (National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science) , John Spyrou (University of Oxford) , James Kelly (University of Leeds) , Jingshan Ren (University of Oxford) , Jonathan Grimes (Division of Structural Biology, University of Oxford) , Gerhard Puerstinger (Department of Pharmaceutical Chemistry, University of Innsbruck) , Nicola Stonehouse (University of Leeds) , Thomas Walter (University of Oxford) , Zhongyu Hu (National Institutes for Food and Drug Control, No. 2, Tiantan Xili, Beijing) , Junzhi Wang (National Institutes for Food and Drug Control, No. 2, Tiantan Xili, Beijing) , Xuemei Li (National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing) , Wei Peng (National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing) , David J Rowlands (University of Leeds) , Liz Fry (University of Oxford) , Zihe Rao (Tsinghua University) , Dave Stuart (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

Open Access Open Access

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

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 26/03/2014 19:01

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