4CDX

Crystal structure of human Enterovirus 71 in complex with the uncoating inhibitor GPP12

Summary for 4CDX

• Entry DOI: 10.2210/pdb4cdx/pdb
• Related: 4CDQ 4CDU 4CDW 4CEW 4CEY
• Descriptor: VP1, VP2, VP3, ... (7 entities in total)
• Functional Keywords: virus, hand-foot-and-mouth disease, enterovirus uncoating, inhibitor
• Biological source: ENTEROVIRUS A71; More
• Total number of polymer chains: 4
• Total formula weight: 94870.89

Authors

De Colibus, L.,Wang, X.,Spyrou, J.A.B.,Kelly, J.,Ren, J.,Grimes, J.,Puerstinger, G.,Stonehouse, N.,Walter, T.S.,Hu, Z.,Wang, J.,Li, X.,Peng, W.,Rowlands, D.,Fry, E.E.,Rao, Z.,Stuart, D.I. (deposition date: 2013-11-07, release date: 2014-02-12, Last modification date: 2024-05-08)

Primary citation

De Colibus, L.,Wang, X.,Spyrou, J.A.B.,Kelly, J.,Ren, J.,Grimes, J.,Puerstinger, G.,Stonehouse, N.,Walter, T.S.,Hu, Z.,Wang, J.,Li, X.,Peng, W.,Rowlands, D.J.,Fry, E.E.,Rao, Z.,Stuart, D.I.
More-Powerful Virus Inhibitors from Structure-Based Analysis of Hev71 Capsid-Binding Molecules.
Nat.Struct.Mol.Biol., 21:282-, 2014

PubMed 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.

PubMed: 24509833
DOI: 10.1038/NSMB.2769

Experimental method

X-RAY DIFFRACTION (2.8 Å)