STRUCTURES OF AROMATIC INHIBITORS OF INFLUENZA-VIRUS NEURAMINIDASE

Neuraminidase (NA), a surface glycoprotein of influenza virus, is a po tential target for design of antiinfluenza agents. The crystal structu re of influenza virus neuraminidase showed that in the active site 11 residues are universally conserved among all strains known so far. Sev eral potent inhibitors based on the carbohydrate compound 2-deoxy-2,3- didehydro-O-N-acetylneuraminic acid (DANA) have been shown to bind to the conserved active site and to reduce virus infection in animals whe n administered by nasal spray. Inhibitors of this type are, however, r apidly excreted from physiological systems and may not be effective in order to provide long-time protection. A new class of specific NA inh ibitors, which are benzoic acid derivatives, has been designed on the basis of the three-dimensional structure of the NA-DANA complex and mo deling of derivatives of 4-(acetylamino)benzoic acid in the NA active site. Intermediates were synthesized and were shown to moderately inhi bit the NA activity and to bind to the NA active site as predicted. Th ese rudimentary inhibitors, 4-(acetylamino)-3-hydroxy-5-nitrobenzoic a cid, 4-(acetylamino)-3-hydroxy-5-aminobenzoic acid, and 4-(acetylamino )-3-aminobenzoic acid, and their X-ray structures in complexes with N2 (A/Tokyo/3/67) and B/Lee/40 neuraminidases have been analyzed. The co ordinates of such inhibitors complexed with NA were used as the starti ng model for further design of more potent benzoic acid inhibitors. Be cause the active site residues of NA are invariant, the designed aroma tic inhibitors have the potential to become an antiviral drug against all strains of influenza virus.