Download MendeleyA sialic acid-derived phosphonate analog inhibits different strains of influenza virus neuraminidase with different efficiencies.
White, C.L., Janakiraman, M.N., Laver, W.G., Philippon, C., Vasella, A., Air, G.M., Luo, M.(1995) J Mol Biol 245: 623-634
- PubMed: 7844831
- Primary Citation of Related Structures:
1INV, 1INW, 1INX, 1INY - PubMed Abstract:
A phosphonate analog of N-acetyl neuraminic acid (PANA) has been designed as a potential neuraminidase (NA) inhibitor and synthesized as both 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-fold better than by sialic acid. The aPANA compound was not a strong inhibitor for any of the NA strains tested. The crystal structures at 2.4 A 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 neither of the PANA compounds distorted the NA active site upon binding. No significant differences in the NA-ePANA complex structures were found to explain the anomalous inhibition of N9 neuraminidase by ePANA. We put forward the hypothesis that an increase in the ePANA inhibition compared to that caused by sialic acid is due to (1) a stronger electrostatic interaction between the inhibitor phosphonyl group and the active site arginine pocket and (2) a lower distortion energy requirement for binding of ePANA.
Organizational Affiliation:
Center for Macromolecular Crystallography, University of Alabama at Birmingham 35294.
