Another look at the molecular mechanism of the resistance of H5N1 influenza A virus neuraminidase (NA) to oseltamivir (OTV)
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 neuraminidaseSource:
Biophysical Chemistry, 2008, 136, 2-3, 152-158Publisher:
- Elsevier Science Bv, Amsterdam
DOI: 10.1016/j.bpc.2008.06.003
ISSN: 0301-4622
PubMed: 18584938
WoS: 000257821400012
Scopus: 2-s2.0-46149126359
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Institution/Community
Institut za tehnologiju nuklearnih i drugih mineralnih sirovinaTY - 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 .