Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus.
The worldwide spread of H5N1 avian influenza and the increasing reports about its resistance to the existing drugs have made a priority for the development of the new anti-influenza molecules. The crystal structure of H5N1 avian influenza neuraminidase reported recently by Russell et al. [R.J. Russell, L.F. Haire, D.J. Stevens, P.J. Collins, Y. P. Lin, G.M. Blackburn, A.J. Hay, S.J. Gamblin, J.J. Skehel, The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design, Nature 443 (2006) 45-49] have provided new opportunities for drug design in this regard. It is revealed through the structure that the active sites of the group-1 neuraminidases, which contain the N1 subtype, have a very different three-dimensional structure from those of group-2 neuraminidases. The key difference is in the 150-loop cavity adjacent to the conserved active site in neuraminidase. Based on these findings and by modifying oseltamivir, six analog inhibitors were proposed as candidates for developing inhibitors against H5N1 virus, particularly against the oseltamivir-resistant H5N1 virus strain.
Du
Qi-Shi
QS
Key Laboratory of Subtropical Bioresource Conservation and Utilization, Guangxi University, Nanning, Guangxi 530004, China.
Wang
Shu-Qing
SQ
Chou
Kuo-Chen
KC
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001717:Birds; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects / Q000201:enzymology*; D005585:Influenza in Birds / Q000517:prevention & control / Q000821:virology; D007251:Influenza, Human / Q000517:prevention & control / Q000821:virology; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D053139:Oseltamivir / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase