title: Molecular mechanism of a specific capsid binder resistance caused by mutations outside the binding pocket.
abstract: 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.
authors.affiliation: Jena University Hospital, School of Medicine, Department of Virology and Antiviral Therapy, Hans-Knöll-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.
authors.forename: Heike
authors.initials: H
authors.lastname: Braun
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom; University of Hamburg, Center for Bioinformatics, Bundesstraße 43, 20146 Hamburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Kirchmair
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Williamson
authors.affiliation: Bakh Institute of Biochemistry, Leninsky pr., 33-2, Moscow 119071, Russia.
authors.forename: Vadim A
authors.initials: VA
authors.lastname: Makarov
authors.affiliation: Bakh Institute of Biochemistry, Leninsky pr., 33-2, Moscow 119071, Russia.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Riabova
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Glen
authors.affiliation: Jena University Hospital, School of Medicine, Department of Virology and Antiviral Therapy, Hans-Knöll-Str. 2, 07745 Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sauerbrei
authors.affiliation: Jena University Hospital, School of Medicine, Department of Virology and Antiviral Therapy, Hans-Knöll-Str. 2, 07745 Jena, Germany. Electronic address: michaela.schmidtke@med.uni-jena.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schmidtke
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D036022:Capsid Proteins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D029822:Enterovirus B, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D020125:Mutation, Missense; D010069:Oxadiazoles / Q000494:pharmacology; D010080:Oxazoles; D011485:Protein Binding; D011487:Protein Conformation; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; D010069:Oxadiazoles; D010080:Oxazoles; C115201:pleconaril
keywords: Antiviral; Computational studies; Drug susceptibility testing; Enterovirus; Pleconaril; Rhinovirus