A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin

Significance Influenza is a contagious and sometimes lethal disease of the human respiratory tract. Current preventative measures include annual vaccination and a limited number of antiviral drugs. However, the effectiveness of the seasonal vaccine is unpredictable, and resistance has been developing to all approved drugs. Therefore, novel influenza therapeutics with new targets and mechanisms are essential to protect against future pandemics, epidemics, and seasonal flu. Here, we report on the serendipitous discovery of a noncarbohydrate-based small-molecule N -cyclohexyltaurine that binds to the receptor-binding site of influenza virus hemagglutinin. Our structural findings provide much needed insights on how to effectively and specifically target the hemagglutinin receptor-binding site with small-molecule ligands, a goal which has evaded researchers for many years.