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Chemical Compound Review

DANA     (4S,5R,6R)-5-acetamido-4- hydroxy-6-[(1R...

Synonyms: CHEMBL96712, CHEBI:28062, D9050_SIGMA, DNC000515, Neu5Ac2en, ...
 
 
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Disease relevance of AIDS121334

  • Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors [1].
  • Neu5Acalpha2Me, Neu5Ac-alpha(2,6)-S-Galbeta1Me, Neu5,9Ac(2)alpha2Me, and Neu5Ac2en inhibited rotavirus infection of MA104 cells by 61%, 35%, 30%, and 0%, respectively, at 10 mM concentration [2].
  • To explore the influence of binding to human parainfluenza virus type 1 (hPIV-1), a series of 4-O-substituted Neu5Ac2en derivatives 6a-e was synthesized and tested for their ability to inhibit hPIV-1 sialidase [3].
  • Herein, we report our studies involving the sialidase from the pathogen Vibrio cholerae, through the modelling, synthesis and biological evaluation of mimetics of 5-acetamido-2,6-anhydro-3,5-dideoxy-D-glycero-D-galacto-non-2-enonic acid (Neu5Ac2en, 1), a naturally occurring sialidase inhibitor [4].
  • N-Acetylneuraminic, 2-deoxy-2,3-didehydro-N-acetylneuraminic acid and the beta anomer of methoxyneuraminic acid (Neu5Ac, Neu5Ac2en, MeONeu) have been used as probes for the catalytic mechanism of the activities of the outer membrane-bound haemagglutinin-neuraminidase (HN) from newcastle disease virus (NDV) [5].
 

High impact information on AIDS121334

  • In this study using alpha-2,3-sialyllactose co-crystallized with VCNA it was revealed that the inhibitor 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en) was bound at the catalytic site [6].
  • Kinetic analysis of 4-guanidino-Neu5Ac2en binding demonstrated that the variant no longer exhibited the slow binding characteristic seen with the parent and other influenza viruses and inhibition by Neu5Ac2en was also decreased [7].
  • Neu5Ac2en but not KDN2en effectively inhibited the hydrolysis of Gg2 by the oyster sialidase [8].
  • This derivative, with a benzyl group added to the O4 position of Neu5Ac2en, has an IC(50) of approximately 10 muM in a neuraminidase assay against hPIV3 HN [9].
  • The sialidase is monomeric and has an average molecular mass of 48500 Da, a pH optimum of 4.6, hydrolyses preferably glycoprotein (fetuin) and sialyllactose, is activated by Ca2 and inhibited by N-acetyl-2,3-dehydro-2- deoxyneuraminic acid ( Neu5Ac2en ), Hg2 and N-(4-nitrophenyl) oxamic acid [10].
 

Associations of AIDS121334 with other chemical compounds

  • Docking experiments using DOCK (version 4.0.1) revealed further information regarding the binding characteristics of the enzyme active site in complex with Neu5Ac2en (2) and the Neu5Ac2en mimetic (3), indicating an expected dominant interaction of the acetamide moiety with the protein [11].

References

  1. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. McKimm-Breschkin, J.L., Sahasrabudhe, A., Blick, T.J., McDonald, M., Colman, P.M., Hart, G.J., Bethell, R.C., Varghese, J.N. J. Virol. (1998) [Pubmed]
  2. STD NMR spectroscopy and molecular modeling investigation of the binding of N-acetylneuraminic acid derivatives to rhesus rotavirus VP8* core. Haselhorst, T., Blanchard, H., Frank, M., Kraschnefski, M.J., Kiefel, M.J., Szyczew, A.J., Dyason, J.C., Fleming, F., Holloway, G., Coulson, B.S., von Itzstein, M. Glycobiology (2007) [Pubmed]
  3. 2-Deoxy-2,3-didehydro-N-acetylneuraminic acid analogues structurally modified at the C-4 position: Synthesis and biological evaluation as inhibitors of human parainfluenza virus type 1. Ikeda, K., Sato, K., Kitani, S., Suzuki, T., Maki, N., Suzuki, Y., Sato, M. Bioorg. Med. Chem. (2006) [Pubmed]
  4. Modelling, synthesis and biological evaluation of novel glucuronide-based probes of Vibrio cholerae sialidase. Mann, M.C., Thomson, R.J., Dyason, J.C., McAtamney, S., von Itzstein, M. Bioorg. Med. Chem. (2006) [Pubmed]
  5. On the inhibition mechanism of the sialidase activity from Newcastle disease virus. García Sastre, A., Cobaleda, C., Cabezas, J.A., Villar, E. Biol. Chem. Hoppe-Seyler (1991) [Pubmed]
  6. Sialic acid recognition by Vibrio cholerae neuraminidase. Moustafa, I., Connaris, H., Taylor, M., Zaitsev, V., Wilson, J.C., Kiefel, M.J., von Itzstein, M., Taylor, G. J. Biol. Chem. (2004) [Pubmed]
  7. Generation and characterization of an influenza virus neuraminidase variant with decreased sensitivity to the neuraminidase-specific inhibitor 4-guanidino-Neu5Ac2en. Blick, T.J., Tiong, T., Sahasrabudhe, A., Varghese, J.N., Colman, P.M., Hart, G.J., Bethell, R.C., McKimm-Breschkin, J.L. Virology (1995) [Pubmed]
  8. A unique sialidase that cleaves the Neu5Gcalpha2-->5-O(glycolyl)Neu5Gc linkage: comparison of its specificity with that of three microbial sialidases toward four sialic acid dimers. Inoue, S., Lin, S.L., Inoue, Y., Groves, D.R., Thomson, R.J., von Itzstein, M., Pavlova, N.V., Li, S.C., Li, Y.T. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  9. Structural analysis of a designed inhibitor complexed with the hemagglutinin-neuraminidase of Newcastle disease virus. Ryan, C., Zaitsev, V., Tindal, D.J., Dyason, J.C., Thomson, R.J., Alymova, I., Portner, A., Itzstein, M., Taylor, G. Glycoconj. J. (2006) [Pubmed]
  10. Isolation and characterization of an oligosaccharide- and glycoprotein-specific sialidase from human leucocytes. Schauer, R., Wember, M., Tschesche, H. Hoppe-Seyler's Z. Physiol. Chem. (1984) [Pubmed]
  11. Saturation transfer difference (STD) 1H-NMR experiments and in silico docking experiments to probe the binding of N-acetylneuraminic acid and derivatives to Vibrio cholerae sialidase. Haselhorst, T., Wilson, J.C., Thomson, R.J., McAtamney, S., Menting, J.G., Coppel, R.L., von Itzstein, M. Proteins (2004) [Pubmed]
 
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