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Potent antiviral agents fail to elicit genetically-stable resistance mutations in either enterovirus 71 or Coxsackievirus A16

DOI: 10.1016/j.antiviral.2015.10.006 DOI Help
PMID: 26522770 PMID Help

Authors: James T. Kelly (University of Leeds) , Luigi De Colibus (University of Oxford) , Lauren Elliott (University of Leeds) , Liz Fry (University of Oxford) , Dave Stuart (Diamond Light Source) , David J. Rowlands (University of Leeds) , Nicola J. Stonehouse (University of Leeds)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Antiviral Research , VOL 124 , PAGES 77 - 82

State: Published (Approved)
Published: December 2015

Open Access Open Access

Abstract: Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are the two major causative agents of hand, foot and mouth disease (HFMD), for which there are currently no licenced treatments. Here, the acquisition of resistance towards two novel capsid-binding compounds, NLD and ALD, was studied and compared to the analogous compound GPP3. During serial passage, EV71 rapidly became resistant to each compound and mutations at residues I113 and V123 in VP1 were identified. A mutation at residue 113 was also identified in CVA16 after passage with GPP3. The mutations were associated with reduced thermostability and were rapidly lost in the absence of inhibitors. In silico modelling suggested that the mutations prevented the compounds from binding the VP1 pocket in the capsid. Although both viruses developed resistance to these potent pocket-binding compounds, the acquired mutations were associated with large fitness costs and reverted to WT phenotype and sequence rapidly in the absence of inhibitors. The most effective inhibitor, NLD, had a very large selectivity index, showing interesting pharmacological properties as a novel anti-EV71 agent.

Journal Keywords: Hand Foot And Mouth Disease; Capsid Binding; Drug Resistance; Fitness; Vp1 Pocket

Subject Areas: Medicine


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Added On: 15/12/2015 15:31

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