Neuraminidase inhibitors design

Jedrzejas, M. J., Singh, S. Brouillette, W. J. Air, G. M. Luo, M. A. 1995. Strategy for theoretical binding constant, Ki calculation for neuraminidase aromatic inhibitors, designed on the basis of the active site structure of influenza virus neuraminidase. Proteins Struct. Funct. Genet. 23 (1995) 264-277... 

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... 

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... 

All the nearest-neighbor interactions between sialic acid or Neu5Ac2en and the protein are with totally conserved amino acids. Thus an inhibitor designed to bind only to the conserved active-site residues of neuraminidase would inhibit neuraminidase activity across all strains of influenza. This would enable the development of an antiviral drug that would affect the spread of viral replication potentially in three ways, i.e., transport through the protective mucosal layer, desialyation of freshly synthesized viral glycoproteins, and elution of progeny virions from infected cells. 

P. M. Colman Design and antiviral properties of influenza virus neuraminidase inhibitors... 

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. 

Genet., 23, 264 (1995). A Strategy for Theoretical Binding Constant, K , Calculations for Neuraminidase Aromatic Inhibitors Designed on the Basis of the Active Site Structure of Influenza Virus Neuraminidase. 

These efforts have culminated in the hve-membered carbocyclic compound peramivir 41, which is an orally available influenza neuraminidase inhibitor, obtained by rational design [90]. In a comprehensive study, 41 has been shown to possess neuraminidase activity comparable with both zanamivir 28 and oseltamivir 35 against a number of influenza strains. Furthermore, 41 was found to be very selective for influenza neuraminidase over mammalian, bacterial or other viral neuraminidases. Peramivir 41 is currently undergoing clinical evaluation as an oral treatment for influenza in humans [90b]. 

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... 

An example is provided by a series of neuraminidase inhibitors leading to the design of the avian flu agent tamiflu. These compounds result from a cyclohexene scaffold containing lipophilic side-chains. ... 

Babu YS, Chand P, Bantia S, Kotian P, Dehghani A, El Kattan Y, Lin TH, Hutchison TL, Elliott AJ, Parker CD, Ananth SL, Horn LL, Laver GW, Montgomery JA. BCX-1812 (RWJ-270201) discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J Med Chem 2000 43 3482-3486. 

Chand P, Babu YS, Bantia S, Chu NM, Cole LB, Kotian PL, Laver WG, Montgomery JA, Pathak VP, Petty SL, Shrout DP, Walsh DA, Walsh GW. Design and synthesis of benzoic acid derivatives as influenza neuraminidase inhibitors using structure-based drug design. J Med Chem 1997 40 4030-4052. 

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