Insights from investigating the interaction of oseltamivir (Tamiflu) with neuraminidase of the 2009 H1N1 swine flu virus.
The neuraminidase (NA) of influenza virus is the target of anti-flu drugs oseltamivir and zanamivir. Clinical practices showed that oseltamivir was effective to treat the 2009-H1N1 influenza but failed to the 2006-H5N1 avian influenza. To perform an in-depth analysis on such a drug-resistance problem, the 2009-H1N1-NA structure was developed. To compare it with the crystal 2006-H5N1-NA structure as well as the 1918 influenza virus H1N1-NA structure, the multiple sequential and structural alignments were performed. It has been revealed that the hydrophobic residue Try347 in H5N1-NA does not match with the hydrophilic carboxyl group of oseltamivir as in the case of H1N1-NA. This may be the reason why H5N1 avian influenza virus is drug-resistant to oseltamivir. The finding provides useful insights for how to modify the existing drugs, such as oseltamivir and zanamivir, making them not only become more effective against H1N1 virus but also effective against H5N1 virus.
Wang
Shu-Qing
SQ
College of Bioinformatics, Chongqing University of Posts and Telecommunications, Chongqing 400065, China.
Du
Qi-Shi
QS
Huang
Ri-Bo
RB
Zhang
Da-Wei
DW
Chou
Kuo-Chen
KC
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D015195:Drug Design; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000201:enzymology*; D007251:Influenza, Human / Q000188:drug therapy / Q000453:epidemiology* / Q000821:virology; D008969:Molecular Sequence Data; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D053139:Oseltamivir / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011487:Protein Conformation
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D053139:Oseltamivir; D009439:Neuraminidase