STRUCTURE-BASED INHIBITORS OF INFLUENZA-VIRUS SIALIDASE - A BENZOIC-ACID LEAD WITH NOVEL INTERACTION

Influenza virus sialidase is a surface enzyme that is essential for in fection of the virus. The catalytic site is highly conserved among all known influenza variants, suggesting that this protein is a suitable target for drug intervention. The most potent known inhibitors are ana logs of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en), par ticularly the 4-guanidino derivative (4-guanidino-Neu5Ac2en). We utili zed the benzene ring of 4-(N-acetylamino)benzoic acids as a cyclic tem plate to substitute for the dihydropyran ring of Neu5Ac2en. In this st udy several 3-(N-acylamino) derivatives were prepared as potential rep lacements for the glycerol side chain of Neu5Ac2en, and some were foun d to interact with the same binding subsite of sialidase. Of greater s ignificance was the observation that the 3-guanidinobenzoic acid deriv ative (equivalent to the 4-guanidino grouping of 4-guanidino-Neu5Ac2en ), the most potent benzoic acid inhibitor of influenza sialidase thus far identified (IC50 = 10 mu M), occupied the glycerol-binding subsite on sialidase as opposed to the guanidino-binding subsite. This benzoi c acid derivative thus provides a new compound that interacts in a nov el manner with the catalytic site of influenza sialidase.