Structural basis for oseltamivir resistance of influenza viruses.
Oseltamivir, one of the two anti-neuraminidase drugs, is currently the most widely used drug against influenza. Resistance to the drug has occurred infrequently among different viruses in response to drug treatment, including A H5N1 viruses, but most notably has emerged among recently circulating A H1N1 viruses and has spread throughout the population in the absence of drug use. Crystal structures of enzyme-drug complexes, together with enzymatic properties, of mutants of H5N1 neuraminidase have provided explanations for high level oseltamivir resistance due to the common H275Y mutation, with retention of zanamivir susceptibility, and intermediate level resistance due to the N295S mutation. Complementation of enhanced NA activity due to a D344N mutation by the H275Y mutation suggests an explanation for the recent emergence and predominance of oseltamivir-resistant influenza A H1N1 viruses.
MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
P J
PJ
Collins
L F
LF
Haire
Y P
YP
Lin
J
J
Liu
R J
RJ
Russell
P A
PA
Walker
S R
SR
Martin
R S
RS
Daniels
V
V
Gregory
J J
JJ
Skehel
S J
SJ
Gamblin
A J
AJ
Hay
D024882:Drug Resistance, Viral; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D009439:Neuraminidase / Q000235:genetics*; D053139:Oseltamivir / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D014764:Viral Proteins / Q000235:genetics*
D014764:Viral Proteins; D053139:Oseltamivir; C487630:NA protein, influenza A virus; D009439:Neuraminidase