Structure Elucidation of Coxsackievirus A16 in Complex with GPP3 Informs a Systematic Review of Highly Potent Capsid Binders to Enteroviruses.
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.
Division of Structural Biology, University of Oxford, Oxford, United Kingdom.
Luigi
L
De Colibus
National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China.
Xiangxi
X
Wang
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
Aloys
A
Tijsma
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
Johan
J
Neyts
Division of Structural Biology, University of Oxford, Oxford, United Kingdom.
John A B
JA
Spyrou
Division of Structural Biology, University of Oxford, Oxford, United Kingdom.
Jingshan
J
Ren
Division of Structural Biology, University of Oxford, Oxford, United Kingdom; Diamond Light Source, Didcot, United Kingdom.
Jonathan M
JM
Grimes
Department of Pharmaceutical Chemistry, University of Innsbruck, Innsbruck, Austria.
Gerhard
G
Puerstinger
Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium.
Pieter
P
Leyssen
Division of Structural Biology, University of Oxford, Oxford, United Kingdom.
Elizabeth E
EE
Fry
National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing, China; Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing, China.
Zihe
Z
Rao
Division of Structural Biology, University of Oxford, Oxford, United Kingdom; Diamond Light Source, Didcot, United Kingdom.
David I
DI
Stuart
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002213:Capsid / Q000378:metabolism; D036022:Capsid Proteins / Q000378:metabolism; D002460:Cell Line; D003384:Coxsackievirus Infections / Q000517:prevention & control; D018360:Crystallography, X-Ray; D029821:Enterovirus A, Human / Q000737:chemistry* / Q000187:drug effects* / Q000648:ultrastructure*; D006801:Humans; D008958:Models, Molecular
D000998:Antiviral Agents; D036022:Capsid Proteins