title: More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules.
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.
authors: Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK.
authors: Luigi
authors: L
authors: De Colibus
authors: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
authors: Xiangxi
authors: X
authors: Wang
authors: Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK.
authors: John A B
authors: JAB
authors: Spyrou
authors: School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
authors: James
authors: J
authors: Kelly
authors: Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK.
authors: Jingshan
authors: J
authors: Ren
authors: Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK.|Diamond Light Sources, Harwell Science and Innovation Campus, Didcot, UK.
authors: Jonathan
authors: J
authors: Grimes
authors: Department of Pharmaceutical Chemistry, University of Innsbruck, Innsbruck, Austria.
authors: Gerhard
authors: G
authors: Puerstinger
authors: School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
authors: Nicola
authors: N
authors: Stonehouse
authors: Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK.
authors: Thomas S
authors: TS
authors: Walter
authors: National Institutes for Food and Drug Control, No. 2, TiantanXili, Beijing, China.
authors: Zhongyu
authors: Z
authors: Hu
authors: National Institutes for Food and Drug Control, No. 2, TiantanXili, Beijing, China.
authors: Junzhi
authors: J
authors: Wang
authors: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
authors: Xuemei
authors: X
authors: Li
authors: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
authors: Wei
authors: W
authors: Peng
authors: School of Molecular and Cellular Biology, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
authors: David
authors: D
authors: Rowlands
authors: Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK.
authors: Elizabeth E
authors: EE
authors: Fry
authors: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China.|Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China.
authors: Zihe
authors: Z
authors: Rao
authors: Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK.|Diamond Light Sources, Harwell Science and Innovation Campus, Didcot, UK.
authors: David I
authors: DI
authors: Stuart
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry; D001665:Binding Sites; D002213:Capsid / Q000737:chemistry*; D036022:Capsid Proteins / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D029821:Enterovirus A, Human / Q000187:drug effects*; D004769:Enterovirus Infections / Q000188:drug therapy / Q000821:virology; D007093:Imidazoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; D007093:Imidazoles; D008024:Ligands