Neuraminidase inhibitor structure

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... 

T., Sham, H.L., Greer, J., and Kempf, D. (2003) Influenza neuraminidase inhibitors structure-based design of a novel inhibitor series. Biochemistry, 42, 718-727. 

B neuraminidase and its complex with sialic acid. Embo J 11 49-56 Burmeister WP, Henrissat B, Bosso C, Cusack S, Ruigrok RW (1993) Influenza B virus neuraminidase can synthesize its own inhibitor. Structure 1 19-26 Calfee DP, Hayden FG (1998) New approaches to influenza chemotherapy neuraminidase inhibitors, Drugs 56 537-553... 

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... 

Burmeister WP, Henrissat B, Bosso C, Cusack S, Ruigrok RWH. Influenza virus neuraminidase can synthesize its own inhibitor. Structure 1993 1 19-26. 

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. 

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. 

Kim, C. U Lew, W Williams, M. A., Wu, H Zhang, L Chen, X., et al. Structure-Activity Relationship Studies of Novel Carbocyclic Influenza Neuraminidase Inhibitors. 

In a structure-based drug-discovery programme in the field of influenza virus neuraminidase inhibitors, researchers at BioCryst Pharmaceuticals discovered aminocarbafuranose sialyl mimetic 89 as a very potent candidate against influenza A and B viruses [17]. To arrive at this highly substituted compound in a non-racemic format, the viable route of Scheme 14 was executed. 

Chandler, M. et al. Approaches to Carbocyclic Analogues of the Potent Neuraminidase Inhibitor 4-Guanidino-Neu5Ac2en. X-Ray Molecular Structure of N-[(/ S,2S, 6R)-2-azido-6-benzyloxy-methyl-4-formylcyclohex-3-enyl]acetamide. 3.4.1 1995 [112]... 

Mendel DB, Laver WG, Stevens RC. Structure—activity relationship studies of novel carbocyclic influenza neuraminidase inhibitors./. Med. Chem., 1998, 41, 2451-2460. 

Figure 6.17. Crystal structure (PDB entry la4q) of the neuraminidase inhibitor zanamivir bound in tltie active site (213).

Fig. 1 The structure of the neuraminidase inhibitor Ro-64-0802 and its ethyl ester prodrug Oseltamivir.

Two agents, oseltamivir and zanamivir, are approved for the management of Influenza A and B infection. Both are potent neuraminidase inhibitors responsible for inhibiting viral replication. These agents differ in their structural compounds, enabling oseltamavir to have greater bioavailabihty and be the only oral option. There have been no reports of nephrotoxicity with the use of either agent. 

Special interest has been taken in the inhibition of enzymes involved in cleaving the glycosidic bonds of neuraminic acid (a complex C9-carbon sugar acid), because this process is critical to the spread of infection after the influenza virus binds to the host cell. Following the analysis of the structure of complexes of the enzyme and substrate (bound in a distorted conformation), unsaturated compounds, for example 43 (Figure 1.14), were made as mimics of the latter in the reaction transition state and found to be potent neuraminidase inhibitors and anti-influenza compounds [49]. 

Several potent influenza neuraminidase inhibitors have been synthesized, and some of them have proven to be effective in treating influenza virus infections in humans. Table 16.5 summarizes the chemical structures and names of these compounds as well as their IC50 values. 

Chemical Structures, Names and IC50 Values of Potent Influenza Neuraminidase Inhibitors... 

A fine example of structure-based drug design has been reported for the design of an influenza virus neuraminidase inhibitor (see Scheme 11). Neuraminidase is an enzyme expressed on the surface of influenza virions and it is thought to be important for the successful release of progeny. Inhibition of... 

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