Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)
Authorized Users Only
Article (Published version)
MetadataShow full item record
In the context of a recent pandemic threat by the worldwide spread of H5N1 avian influenza, the high resistance of H5N1 virus to the most widely used commercial drug, oseltarnivir (Tamiflu), is currently an important research topic. Herein, molecular bases of the mechanism of H5N1 NA resistance to orseltarnivir were elucidated using a computational approach in a systematic fashion. Using the crystal structure of the complex of H5N1 NAwith OTV (PDB ID: 2hu0) as the starting point, the question, how mutations at His274 by both smaller side chain (Gly, Set, Asn, Gln) and larger side chain (Phe, Tyr) residues influence the sensitivity of N1 to orseltarnivir, was addressed and correlated with the experimental data. The smaller side chain residue mutations of His;274 resulted in slightly enhanced or unchanged NA sensitivity to OTV, while His274Phe and His274Tyr reduced the susceptibility of OTV to N1. In contrast to the binding free energies, the net charges of Glu276 and Arg224, making char...ge-charge interactions with Glu276, were established to be more sensitive to detecting subtle conformational differences induced at the key residue Glu276 by the His274X mutations. This study provides deeper insights into the possibility of developing viable drug-resistant mutants.
Keywords:resistance / oseltamivir / mutants / influenza a virus / H5N1 neuraminidase
Source:Biophysical Chemistry, 2008, 136, 2-3, 152-158
- Elsevier Science Bv, Amsterdam