Search

Your search keyword '"John A B Spyrou"' showing total 2 results
Start Over Author "John A B Spyrou"
2 results on '"John A B Spyrou"'

1. Structure Elucidation of Coxsackievirus A16 in Complex with GPP3 Informs a Systematic Review of Highly Potent Capsid Binders to Enteroviruses.

Author

Luigi De Colibus, Xiangxi Wang, Aloys Tijsma, Johan Neyts, John A B Spyrou, Jingshan Ren, Jonathan M Grimes, Gerhard Puerstinger, Pieter Leyssen, Elizabeth E Fry, Zihe Rao, and David I Stuart

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

The replication of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), which are the major cause of hand, foot and mouth disease (HFMD) in children, can be inhibited by the capsid binder GPP3. Here, we present the crystal structure of CVA16 in complex with GPP3, which clarifies the role of the key residues involved in interactions with the inhibitor. Based on this model, in silico docking was performed to investigate the interactions with the two next-generation capsid binders NLD and ALD, which we show to be potent inhibitors of a panel of enteroviruses with potentially interesting pharmacological properties. A meta-analysis was performed using the available structural information to obtain a deeper insight into those structural features required for capsid binders to interact effectively and also those that confer broad-spectrum anti-enterovirus activity.

Published
2015
Full Text
View/download PDF

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

Author

Nicola J. Stonehouse, Gerhard Puerstinger, Jonathan M. Grimes, J. Kelly, Luigi De Colibus, Xiangxi Wang, Junzhi Wang, Wei Peng, Zihe Rao, Elizabeth E. Fry, Jingshan Ren, David J. Rowlands, Xuemei Li, David I. Stuart, John A. B. Spyrou, Thomas S. Walter, and Zhongyu Hu

Subjects
Protein Conformation, viruses, Chemistry, Pharmaceutical, Chemical biology, Plasma protein binding, Biology, Ligands, Antiviral Agents, Virus, Article, Inhibitory Concentration 50, Structure-Activity Relationship, Protein structure, Capsid, Structural Biology, Enterovirus Infections, Structure–activity relationship, Binding site, Molecular Biology, Binding Sites, Drug discovery, Imidazoles, Virology, 3. Good health, Enterovirus A, Human, Drug Design, Capsid Proteins, Protein Binding
Abstract

Enterovirus 71 (HEV71) epidemics amongst 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 (IC50 = 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.

Published
2014

Catalog

Books, media, physical & digital resources
See catalog results