A SIALIC ACID-DERIVED PHOSPHONATE ANALOG INHIBITS DIFFERENT STRAINS OF INFLUENZA-VIRUS NEURAMINIDASE WITH DIFFERENT EFFICIENCIES

A phosphonate analog of N-acetyl neuraminic acid (PANA) has been desig ned as a potential neuraminidase (NA) inhibitor and synthesized as bot h the alpha (ePANA) and beta (aPANA) anomers. Inhibition of type A (N2 ) and type B NA activity by ePANA was approximately a 100-fold better than by sialic acid, but inhibition of type A (N9) NA was only ten-fol d better than by sialic acid. The aPANA compound was not a strong inhi bitor for any of the NA strains tested. The crystal structures at 2.4 Angstrom resolution of ePANA complexed to type A (N2) NA, type A (N9) NA and type B NA and aPANA complexed to type A (N2) NA showed that nei ther of the PANA compounds distorted the NA active site upon binding. No significant differences in the NA-ePANA complex structures were fou nd to explain the anomalous inhibition of N9 neuraminidase by ePANA. W e put forward the hypothesis that an increase in the ePANA inhibition compared to that caused bysialic acid is due to (1) a stronger electro static interaction between the inhibitor phosphonyl group and the acti ve site arginine pocket and (2) a lower distortion energy requirement for binding of ePANA.