Structural biology: health and food security
Structural biology historically and still has an important role in facing important societal challenges in health and food security. In that tradition, we have just published an article on inhibitors designed against Enterovirus 71 (HEV71) responsible for hand, foot and mouth disease virus . It was the crystal structure determination of the HEV71 particle (1) that provided the opportunity for rational improvement of inhibitors to counter this disease.
HEV71 harbours within its capsid 60 copies of a “pocket factor”, a natural lipid (sphingosine), buried in a pocket lying at the base of the ‘canyon’, in the capsid protein VP1. Expulsion of this molecule following binding of the virus to its receptor triggers release of the viral genomic material. Since expulsion of the pocket factor is required for infection, a tight replacement binder could provide a useful anti-viral drug. Using the molecular skeletons of Pleconaril and related molecules, a novel class of imidazolidinones has been synthesized with anti-HEV71 activity (2,3).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 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 (IC50 = 25 pM) is an order of magnitude more potent than the best previously reported inhibitor, and is also more soluble.
Our approach may provide a powerful platform for the structural design of effective drugs for enterovirus infections (4).
(1) Wang, X.et al. (2012) Nature structural & molecular biology 19, 424-429. (2) Shia, K. S.et al. (2002)Journal of medicinal chemistry 45, 1644-1655. (3) Ke, Y. Y. & Lin, T. H. (2006) Journal of medicinal chemistry 49, 4517-4525 (4) De Colibus L. et al. (2014) Nature structural & molecular biology 21, 282-8
Collaborators: Xiangxi Wang2,‡, John A. B. Spyrou1, James Kelly3, Jingshan Ren1, Jonathan Grimes1,4, Gerhard Puerstinger5, Nicola Stonehouse3,Thomas S. Walter1, Zhongyu Hu6, Junzhi Wang6, Xuemei Li2, Wei Peng2,David Rowlands3, Elizabeth E. Fry1, Zihe Rao2,7*, David I. Stuart1,4*.
1Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, UK, 2National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China, 3School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK,4Diamond Light Sources, Harwell Science and Innovation Campus, Didcot, UK, 5Department of Pharmaceutical Chemistry, University of Innsbruck, Innsbruck,Austria,6National Institutes for Food and Drug Control, No. 2, TiantanXili, Beijing, China,7Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China.