Design and synthesis of novel influenza M2 proton channel inhibitors with drug resistant antiviral activity
Seasonal influenza causes significant mortality and morbidity worldwide, and we are currently unprepared to mitigate a fatal pandemic outbreak like the 1918 Spanish Flu. A proven influenza antiviral target is the M2 viroporin, or viral ion channel. Amantadine, an M2 inhibitor was an effective antiviral for 20 years. However, current influenza antivirals are increasingly ineffective as viruses develop resistance. For example, the M2 mutation S31N is now present in >90% of influenza strains and confers resistance to adamantanes. Thus new M2 inhibitors that block S31N strains are urgently needed. This project aims to design and test new compounds to inhibit adamantine-resistant M2 and determine whether effective M2 inhibitors translate into effective antivirals. Additionally, we will investigate whether sequence variations in M2 impact drug efficacy. This work will benefit our industrial partner Cardiome and the public scientific community by generating both novel therapeutic leads and an increased understanding of M2 biophysics.