| Title | Molecular mechanism of a specific capsid binder resistance caused by mutations outside the binding pocket. | ||
| Author | Braun, Heike; Kirchmair, Johannes; Williamson, Mark J; Makarov, Vadim A; Riabova, Olga B; Glen, Robert C; Sauerbrei, Andreas; Schmidtke, Michaela | ||
| Journal | Antiviral Res | Publication Year/Month | 2015-Nov |
| PMID | 26391975 | PMCID | -N/A- |
| Affiliation + expend | 1.Jena University Hospital, School of Medicine, Department of Virology and Antiviral Therapy, Hans-Knoll-Str. 2, 07745 Jena, Germany; Department of Clinical Pharmacy and Pharmacotherapy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, D-06120 Halle (Saale), Germany. | ||
Enteroviruses cause various acute and chronic diseases. The most promising therapeutics for these infections are capsid-binding molecules. These can act against a broad spectrum of enteroviruses, but emerging resistant virus variants threaten their efficacy. All known enterovirus variants with high-level resistance toward capsid-binding molecules have mutations of residues directly involved in the formation of the hydrophobic binding site. This is a first report of substitutions outside the binding pocket causing this type of drug resistance: I1207K and I1207R of the viral capsid protein 1 of coxsackievirus B3. Both substitutions completely abolish the antiviral activity of pleconaril (a capsid-binding molecule) but do not affect viral replication rates in vitro. Molecular dynamics simulations indicate that the resistance mechanism is mediated by a conformational rearrangement of R1095, which is a neighboring residue of 1207 located at the heel of the binding pocket. These insights provide a basis for the design of resistance-breaking inhibitors.