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Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains.
- Source :
-
Scientific reports [Sci Rep] 2017 Sep 26; Vol. 7 (1), pp. 12336. Date of Electronic Publication: 2017 Sep 26. - Publication Year :
- 2017
-
Abstract
- Influenza is an annual seasonal epidemic that has continually drawn public attentions, due to the potential death toll and drug resistance. Neuraminidase, which is essential for the spread of influenza virus, has been regarded as a valid target for the treatment of influenza infection. Although neuraminidase drugs have been developed, they are susceptible to drug-resistant mutations in the sialic-binding site. In this study, we established computational models (site-moiety maps) of H1N1 and H5N1 to determine properties of the 150-cavity, which is adjacent to the drug-binding site. The models reveal that hydrogen-bonding interactions with residues R118, D151, and R156 and van der Waals interactions with residues Q136, D151, and T439 are important for identifying 150-cavitiy inhibitors. Based on the models, we discovered three new inhibitors with IC <subscript>50</subscript> values <10 μM that occupies both the 150-cavity and sialic sites. The experimental results identified inhibitors with similar activities against both wild-type and dual H274Y/I222R mutant neuraminidases and showed little cytotoxic effects. Furthermore, we identified three new inhibitors situated at the sialic-binding site with inhibitory effects for normal neuraminidase, but lowered effects for mutant strains. The results suggest that the new inhibitors can be used as a starting point to combat drug-resistant strains.
- Subjects :
- Antiviral Agents therapeutic use
Binding Sites genetics
Computer Simulation
Drug Resistance, Viral drug effects
Drug Resistance, Viral genetics
Humans
Influenza A Virus, H1N1 Subtype drug effects
Influenza A Virus, H1N1 Subtype genetics
Influenza A Virus, H1N1 Subtype metabolism
Influenza A Virus, H5N1 Subtype drug effects
Influenza A Virus, H5N1 Subtype genetics
Influenza A Virus, H5N1 Subtype metabolism
Influenza, Human virology
Inhibitory Concentration 50
Mutation
Neuraminidase chemistry
Neuraminidase genetics
Protein Structure, Tertiary
Viral Proteins chemistry
Viral Proteins genetics
Antiviral Agents pharmacology
Drug Discovery methods
Influenza, Human drug therapy
Molecular Dynamics Simulation
Neuraminidase antagonists & inhibitors
Viral Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 28951584
- Full Text :
- https://doi.org/10.1038/s41598-017-12101-3