Kelly, JT, De Colibus, L, Elliott, L et al. (4 more authors) (2015) Potent antiviral agents fail to elicit genetically-stable resistance mutations in either enterovirus 71 or Coxsackievirus A16. Antiviral Research, 124. 77 - 82. ISSN 0166-3542
Abstract
Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16) are the two major causative agents 13 of hand, foot and mouth disease (HFMD), for which there are currently no licenced 14 treatments. Here, the acquisition of resistance towards two novel capsid-binding compounds, 15 NLD and ALD, was studied and compared to the analogous compound GPP3. During serial 16 passage, EV71 rapidly became resistant to each compound and mutations at residues I113 17 and V123 in VP1 were identified. A mutation at residue 113 was also identified in CVA16 18 after passage with GPP3. The mutations were associated with reduced thermostability and 19 were rapidly lost in the absence of inhibitors. In silico modelling suggested that the mutations 20 prevented the compounds from binding the VP1 pocket in the capsid. Although both viruses 21 developed resistance to these potent pocket-binding compounds, the acquired mutations were 22 associated with large fitness costs and reverted to WT phenotype and sequence rapidly in the 23 absence of inhibitors. The most effective inhibitor, NLD, had a very large selectivity index, 24 showing interesting pharmacological properties as a novel anti-EV71 agent.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | Hand, foot and mouth disease; capsid binding; drug resistance; fitness; VP1 pocket |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 21 Oct 2015 09:07 |
Last Modified: | 17 Jan 2018 10:57 |
Published Version: | http://dx.doi.org/10.1016/j.antiviral.2015.10.006 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.antiviral.2015.10.006 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:91037 |