title: How do aminoadamantanes block the influenza M2 channel, and how does resistance develop?
abstract: The interactions between channels and their cognate blockers are at the heart of numerous biomedical phenomena. Herein, we unravel one particularly important example bearing direct pharmaceutical relevance: the blockage mechanism of the influenza M2 channel by the anti-flu amino-adamantyls (amantadine and rimantadine) and how the channel and, consequently, the virus develop resistance against them. Using both computational analyses and experimental verification, we find that amino-adamantyls inhibit M2's H(+) channel activity by electrostatic hindrance due to their positively charged amino group. In contrast, the hydrophobic adamantyl moiety on its own does not impact conductivity. Additionally, we were able to uncover how mutations in M2 are capable of retaining drug binding on the one hand yet rendering the protein and the mutated virus resistant to amino-adamantyls on the other hand. We show that the mutated, drug-resistant protein has a larger binding pocket for the drug. Hence, despite binding the channel, the drug remains sufficiently mobile so as not to exert a H(+)-blocking positive electrostatic hindrance. Such insight into the blocking mechanism of amino-adamantyls, and resistance thereof, may aid in the design of next-generation anti-flu agents.
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmund J. Safra Campus, Jerusalem 91904, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Leonov
authors.forename: Peleg
authors.initials: P
authors.lastname: Astrahan
authors.forename: Miriam
authors.initials: M
authors.lastname: Krugliak
authors.forename: Isaiah T
authors.initials: IT
authors.lastname: Arkin
mesh_terms: D000218:Adamantane / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000547:Amantadine; D000998:Antiviral Agents; D001665:Binding Sites / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics*; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000235:genetics; D009154:Mutation; D012299:Rimantadine; D055672:Static Electricity; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000086082:Viroporin Proteins
chemical_list: D000218:Adamantane; D000547:Amantadine; D000998:Antiviral Agents; D007473:Ion Channels; D012299:Rimantadine; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins