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Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)

Authorized Users Only
2008
Authors
Mihajlović, Marija
Mitrašinović, Petar M.
Article (Published version)
Metadata
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Abstract
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
Publisher:
  • Elsevier Science Bv, Amsterdam

DOI: 10.1016/j.bpc.2008.06.003

ISSN: 0301-4622

PubMed: 18584938

WoS: 000257821400012

Scopus: 2-s2.0-46149126359
[ Google Scholar ]
26
23
URI
https://ritnms.itnms.ac.rs/handle/123456789/143
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Institut za tehnologiju nuklearnih i drugih mineralnih sirovina
TY  - JOUR
AU  - Mihajlović, Marija
AU  - Mitrašinović, Petar M.
PY  - 2008
UR  - https://ritnms.itnms.ac.rs/handle/123456789/143
AB  - 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 charge-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.
PB  - Elsevier Science Bv, Amsterdam
T2  - Biophysical Chemistry
T1  - Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)
EP  - 158
IS  - 2-3
SP  - 152
VL  - 136
DO  - 10.1016/j.bpc.2008.06.003
UR  - conv_546
ER  - 
@article{
author = "Mihajlović, Marija and Mitrašinović, Petar M.",
year = "2008",
abstract = "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 charge-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.",
publisher = "Elsevier Science Bv, Amsterdam",
journal = "Biophysical Chemistry",
title = "Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)",
pages = "158-152",
number = "2-3",
volume = "136",
doi = "10.1016/j.bpc.2008.06.003",
url = "conv_546"
}
Mihajlović, M.,& Mitrašinović, P. M.. (2008). Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV). in Biophysical Chemistry
Elsevier Science Bv, Amsterdam., 136(2-3), 152-158.
https://doi.org/10.1016/j.bpc.2008.06.003
conv_546
Mihajlović M, Mitrašinović PM. Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV). in Biophysical Chemistry. 2008;136(2-3):152-158.
doi:10.1016/j.bpc.2008.06.003
conv_546 .
Mihajlović, Marija, Mitrašinović, Petar M., "Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)" in Biophysical Chemistry, 136, no. 2-3 (2008):152-158,
https://doi.org/10.1016/j.bpc.2008.06.003 .,
conv_546 .

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