Potent antiviral agents fail to elicit genetically-stable resistance mutations in either enterovirus 71 or Coxsackievirus A16
| Autor: | Elizabeth E. Fry, Nicola J. Stonehouse, J. Kelly, Luigi De Colibus, David I. Stuart, Lauren Elliott, David J. Rowlands |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Protein Conformation Short Communication viruses Hand foot and mouth disease MTT 3-(4 5-Dimethylthiazol-2-Yl)-2 5-Diphenyltetrazolium Bromide Drug resistance Crystallography X-Ray medicine.disease_cause Antiviral Agents CC50 Half maximal cytotoxic concentration Cell Line Capsid binding Capsid TCID50 Half-maximal tissue culture infective dose Serial passage Virology Drug Resistance Viral Fitness Enterovirus 71 medicine Animals Humans Vero Cells Enterovirus CVB Coxsackie virus B Pharmacology Mutation biology CVA16 Coxsackie virus A16 WT Wild Type biology.organism_classification Phenotype Enterovirus A Human PV poliovirus Vero cell Capsid Proteins IC50 Half-maximal inhibitory concentration EV71 Enterovirus 71 Hand Foot and Mouth Disease VP1 pocket VP1 Viral Protein 1 |
| Zdroj: | Antiviral Research |
| ISSN: | 0166-3542 |
| DOI: | 10.1016/j.antiviral.2015.10.006 |
| Popis: | 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. Highlights • Resistance to each compound developed rapidly, mutations at residues I113 and V123 were identified. • Resistance mutations were associated with a large fitness cost. • The mutations resulted in reduced affinity for the pocket factor. • The most effective inhibitor, NLD, had a very large therapeutic window, and has potential as a novel anti-EV71 agent. |
| Databáze: | OpenAIRE |
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