Influenza neuraminidase

Neuraminidase inhibitors are the major class of drugs to treat or to prevent the infection with influenza viruses. Currently, two neuraminidase inhibitors are available, zanamivir and oseltamivir, which block the release of new influenza vims from infected host cells and thereby stop the spread of infection. The enzyme neuraminidase is a surface glycoprotein present on all influenza viruses. There are nine influenza neuraminidase sub-types known of which subtypes N1 and N2 appear to be the most important ones. Neuraminidase inhibitors are effective against all neuraminidase subtypes. The activity of the neuraminidase is required for the newly... 

Abed Y, Nehmd B, Baz M, Boivin G (2008) Activity of the neuraminidase inhibitor A-315675 against oseltamivir-resistant influenza neuraminidases of N1 and N2 subtypes. Antiviral Res 77 163-166... 

Chand P, Kotian PL, Morris PE, Bantia S, Walsh DA, Babu YS (2005b) Synthesis and inhibitory activity of benzoic add and pyridine derivatives on influenza neuraminidase. Bioorg Med Chem 13 2665-2678... 

Kim CU, Lew W, Wilhams MA, Liu H, Zhang L, Swaminathan S, Bischofberger N, Chen MS, Mendel DB, Tai CY, Laver WG, Stevens RC (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 119 681-690... 

Kim CU, Lew W, Wilhams MA, Wu H, Zhang L, Chen X, Escarpe PA, Mendel DB, Laver WG, Stevens RC (1998) Structure-activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors, J Med Chem 41 2451-2460 Kim CU, Chen X, Mendel DB (1999) Neuraminidase inhibitors as anti-influenza virus agents. Antiviral Chem Chemother 10 141-154... 

Stoll V, Stewart KD, Mating CJ, Muchmore S, Giranda V, Gu Y-GY, Wang G, Chen Y, Sun M, Zhao C, Kennedy AL, Madigan DL, Xu Y, Saldivar A, Kati W, Laver G, Sowin T, Sham HL, Greer J, Kempf D (2003) Influenza neuraminidase inhibitors structure-based design of a novel inhibitor series. Biochemistry 42 718-727... 

Wang, T. and Wade, R.C. Comparative binding energy (COMBINE) analysis of influenza neuraminidase-inhibitor complexes./. Med. Chem. 2001, 44, 961-971. 

The influenza neuraminidase is one of two major glycoproteins located on the influenza virus membrane envelope (the other one is haemagglutinin, HA). As the name suggests. 

Crystals of pronase-released heads of the N2 human strains of A/Tokyo/3/67 [44] and A/RI/5+/57 were used for an x-ray structure determination. The x-ray 3-dimensional molecular structure of neuraminidase heads was determined [45] for these two N2 subtypes by a novel technique of molecular electron density averaging from two different crystal systems, using a combination of multiple isomorphous replacement and noncrystallographic symmetry averaging. The structure of A/Tokyo/3/67 N2 has been refined [46] to 2.2 A as has the structures of two avian N9 subtypes [47-49]. Three influenza type structures [50] have also been determined and found to have an identical fold with 60 residues (including 16 conserved cysteine residues) being invariant. Bacterial sialidases from salmonella [51] and cholera [52] have homologous structures to influenza neuraminidase, but few of the residues are structurally invariant. 

M. Chandler, M. J. Bamford, R. Conroy, B. Lamont, B. Patel, V. K. Patel, I. P. Steeples, R. Storer, N. G. Weir, M. Wright, and C. Williamson, Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino Neu5Ac2en. X-ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D- rrt/fro-L-g/Mco-nonionic acid, J. Chem. Soc. Perkin Trans., 1 (1995) 1173-1180. 

M. R. Lentz, R. G. Webster, and G. M. Air, Site-directed mutation of the active site of influenza neuraminidase and implications for the catalytic mechanism, Biochemistry, 26 (1987) 5351-5358. 

W. J. Brouillette, V. R. Atigadda, F. Duarte, M. Luo, G. M. Air, Y. S. Babu, and S. Bantia, Design of benzoic acid inhibitors of influenza neuraminidase containing a cyclic substitution for the /V-acctyl grouping. (Erratum to document cited in CA131 266560), Bioorg. Med. Chem. Lett., 9 (1999) 3259. 

M. Williams, N. Bischofberger, S. Swaminathan, and C. U. Kim, Synthesis and influenza neuraminidase inhibitory activity of aromatic analogs of sialic acid, Bioorg. Med. Chem. Lett., 5 (1995) 2251-2254. 

S. Abrecht, P. Harrington, H. Iding, M. Karpf, R. Trussardi, B. Wirz, and U. Zutter, The synthetic development of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu) A challenge for synthesis process research, Chimia, 58 (2004) 621-929. 

G. T. Wang, Y. Chen, S. Wang, R. Gentles, T. Sowin, W. Kati, S. Muchmore, V. Giranda, K. Stewart, H. Sham, D. Kempf, and W. G. Laver, Design, synthesis, and structural analysis of influenza neuraminidase inhibitors containing pyrrolidine cores, J. Med. Chem., 44 (2001) 1192-1201. 

---