ABCMdb

ABCD1 p.Val123Ile

Predicted by SNAP2:	A: D (80%), C: D (80%), D: D (91%), E: D (91%), F: D (85%), G: D (91%), H: D (91%), I: D (80%), K: D (95%), L: D (91%), M: D (85%), N: D (91%), P: D (91%), Q: D (91%), R: D (95%), S: D (91%), T: D (85%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D,

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Publications
[hide] Potent antiviral agents fail to elicit genetically... Antiviral Res. 2015 Dec;124:77-82. doi: 10.1016/j.antiviral.2015.10.006. Epub 2015 Oct 30. Kelly JT, De Colibus L, Elliott L, Fry EE, Stuart DI, Rowlands DJ, Stonehouse NJ
Potent antiviral agents fail to elicit genetically-stable resistance mutations in either enterovirus 71 or Coxsackievirus A16.
Antiviral Res. 2015 Dec;124:77-82. doi: 10.1016/j.antiviral.2015.10.006. Epub 2015 Oct 30., [PMID:26522770]

Abstract [show]
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.

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Sentences [show]
No. Sentence Comment
26 Sequencing revealed three different VP1 mutants in EV71 (I113L, I113M, I113M/V123I) and one in CVA16 (L113F) (Table 1). Login to comment
27 Virus passaged in a combination of NLD/ GPP3 over 30 passages maintained the I113M/V123I mutations (n &#bc; 1). Login to comment
30 Mutations I113M and V123I are located on the inside of the VP1 pocket and I113 is one of the residues involved in compound binding (Fig. 2B). Login to comment
35 The difference in the lowest free energy of folding (DDGfolding) between the WT and EV71 I113M or V123I mutants was &#fe;0.73 and &#fe; 0.98 kcal/mol, respectively. Login to comment
37 The mutations I113M and V123I appeared to cause a shrinking of the VP1 pocket, with the methionine residue pointing inside, suggesting a steric clash with the Fig. 1. Login to comment
52 Virus/Compound Mutation(s) Number sequenced EV71/NLD I113M (62%), I113L (31%), I113M/V123I (7%) n &#bc; 13 EV71/GPP3 I113M/V123I n &#bc; 4 EV71/ALD I113M/V123I n &#bc; 1 EV71/NLD &#fe; GPP3 I113M/V123I n &#bc; 12 CVA16/GPP3 L113F n &#bc; 10 Fig. 2. Login to comment
62 The two mutated side chains I113M and V123I are shown as grey balls-and-sticks. Login to comment
73 These data suggest that the I113M/V123I mutation prevented compound binding as the thermostability of the resistant isolates was not increased in the presence of NLD. Login to comment
74 The bulkier side chains of the I113M and L113F mutations are predicted to point directly into the pocket, reducing the space available for inhibitor binding and the V123I mutation reduces this further. Login to comment