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Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains
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 neur...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615050/ https://www.ncbi.nlm.nih.gov/pubmed/28951584 http://dx.doi.org/10.1038/s41598-017-12101-3 |
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author | Hsu, Kai-Cheng Hung, Hui-Chen HuangFu, Wei-Chun Sung, Tzu-Ying Eight Lin, Tony Fang, Ming-Yu Chen, I-Jung Pathak, Nikhil Hsu, John T.-A. Yang, Jinn-Moon |
author_facet | Hsu, Kai-Cheng Hung, Hui-Chen HuangFu, Wei-Chun Sung, Tzu-Ying Eight Lin, Tony Fang, Ming-Yu Chen, I-Jung Pathak, Nikhil Hsu, John T.-A. Yang, Jinn-Moon |
author_sort | Hsu, Kai-Cheng |
collection | PubMed |
description | 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(50) 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. |
format | Online Article Text |
id | pubmed-5615050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56150502017-10-11 Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains Hsu, Kai-Cheng Hung, Hui-Chen HuangFu, Wei-Chun Sung, Tzu-Ying Eight Lin, Tony Fang, Ming-Yu Chen, I-Jung Pathak, Nikhil Hsu, John T.-A. Yang, Jinn-Moon Sci Rep Article 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(50) 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. Nature Publishing Group UK 2017-09-26 /pmc/articles/PMC5615050/ /pubmed/28951584 http://dx.doi.org/10.1038/s41598-017-12101-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Hsu, Kai-Cheng Hung, Hui-Chen HuangFu, Wei-Chun Sung, Tzu-Ying Eight Lin, Tony Fang, Ming-Yu Chen, I-Jung Pathak, Nikhil Hsu, John T.-A. Yang, Jinn-Moon Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains |
title | Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains |
title_full | Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains |
title_fullStr | Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains |
title_full_unstemmed | Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains |
title_short | Identification of neuraminidase inhibitors against dual H274Y/I222R mutant strains |
title_sort | identification of neuraminidase inhibitors against dual h274y/i222r mutant strains |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5615050/ https://www.ncbi.nlm.nih.gov/pubmed/28951584 http://dx.doi.org/10.1038/s41598-017-12101-3 |
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