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_name
Antiviral Resjournal_title
Antiviral researchauthors
Kelly JT,De Colibus L,Elliott L,Fry EE,Stuart DI,Rowlands DJ,Stonehouse NJdoi
10.1016/j.antiviral.2015.10.006subject
Has Abstractpub_date
2015-12-01 00:00:00pages
77-82eissn
0166-3542issn
1872-9096pii
S0166-3542(15)30004-8journal_volume
124pub_type
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