Amantadine Analogs that Inhibit Mdck Cell Infection by Influenza a with M2(S31N)

Abstract

A mutation of Ser31 to Asn has become dominant globally in human infections by influenza A since 2005, rendering the virus resistant to the FDA approved prophylactics, amantadine and rimantadine. Attempts to identify alternative M2 blockers have reportedly been futile so far. Here we report that infection of cultured Madin-Darby canine kidney cells by Influenza A/California/04/2009 (H1N1 swine flu), which bears the S31N mutation, is not blocked effectively by amantadine (115 μM EC50) nor rimantadine (56 μM EC50), but is effectively blocked by 11 amantadine variants. EC50s range from 1-37 μM. 8 of these 11 compounds were previously reported to block influenza A with wild type M2. As another control, an H3N2 strain of influenza A with wild type M2 (Strain Victoria from ATCC) was found to be effectively blocked by amantadine (3 μM EC50) and rimantadine, as expected. We suggest that the amantadine variants block viral reproduction by blocking the S31N strain of the M2 proton channel.