60033-38-7Relevant academic research and scientific papers
Inhibitors Of The Influenza A Virus M2 Proton Channel
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Page/Page column 8-10, (2012/02/06)
Provided are compounds that are capable of modulating the activity of the influenza A virus via interaction with the M2 transmembrane protein. Also provided are methods for treating an influenza A-affected disease state or infection comprising administering a composition comprising one or more compounds that have been identified as being capable of interaction with the M2 protein.
Molecular dynamics simulation directed rational design of inhibitors targeting drug-resistant mutants of influenza A virus M2
Wang, Jun,Ma, Chunlong,Fiorin, Giacomo,Carnevale, Vincenzo,Wang, Tuo,Hu, Fanghao,Lamb, Robert A.,Pinto, Lawrence H.,Hong, Mei,Klein, Michael L.,Degrado, William F.
supporting information; experimental part, p. 12834 - 12841 (2011/10/08)
Influenza A virus M2 (A/M2) forms a homotetrameric proton selective channel in the viral membrane. It has been the drug target of antiviral drugs such as amantadine and rimantadine. However, most of the current virulent influenza A viruses carry drug-resistant mutations alongside the drug binding site, such as S31N, V27A, and L26F, etc., each of which might be dominant in a given flu season. Among these mutations, the V27A mutation was prevalent among transmissible viruses under drug selection pressure. Until now, V27A has not been successfully targeted by small molecule inhibitors, despite years of extensive medicinal chemistry research efforts and high throughput screening. Guided by molecular dynamics (MD) simulation of drug binding and the influence of drug binding on the dynamics of A/M2 from earlier experimental studies, we designed a series of potent spirane amine inhibitors targeting not only WT, but also both A/M2-27A and L26F mutants with IC50s similar to that seen for amantadine's inhibition of the WT channel. The potencies of these inhibitors were further demonstrated in experimental binding and plaque reduction assays. These results demonstrate the power of MD simulations to probe the mechanism of drug binding as well as the ability to guide design of inhibitors of targets that had previously appeared to be undruggable.
