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Drug Discovery of Host CLK1 Inhibitors for Influenza Treatment

1,2,†, 1,†, 1, 1, 1,3,4,*, 5,* and 1,3,4,*
1
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
2
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
3
Beijing Key Laboratory of Drug Target Research and New Drug Screening, Beijing 100050, China
4
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing 100050, China
5
National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: James W. Leahy and Derek J. McPhee
Molecules 2015, 20(11), 19735-19747; https://doi.org/10.3390/molecules201119653
Received: 11 August 2015 / Revised: 28 September 2015 / Accepted: 21 October 2015 / Published: 2 November 2015
(This article belongs to the Section Medicinal Chemistry)
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PDF [3279 KB, uploaded 2 November 2015]
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Abstract

The rapid evolution of influenza virus makes antiviral drugs less effective, which is considered to be a major bottleneck in antiviral therapy. The key proteins in the host cells, which are related with the replication cycle of influenza virus, are regarded as potential drug targets due to their distinct advantage of lack of evolution and drug resistance. Cdc2-like kinase 1 (CLK1) in the host cells is responsible for alternative splicing of the M2 gene of influenza virus during influenza infection and replication. In this study, we carried out baculovirus-mediated expression and purification of CLK1 and established a reliable screening assay for CLK1 inhibitors. After a virtual screening of CLK1 inhibitors was performed, the activities of the selected compounds were evaluated. Finally, several compounds with strong inhibitory activity against CLK1 were discovered and their in vitro anti-influenza virus activities were validated using a cytopathic effect (CPE) reduction assay. The assay results showed that clypearin, corilagin, and pinosylvine were the most potential anti-influenza virus compounds as CLK1 inhibitors among the compounds tested. These findings will provide important information for new drug design and development in influenza treatment, and CLK1 may be a potent drug target for anti-influenza drug screening and discovery. View Full-Text
Keywords: influenza A virus; CLK1 inhibitor; CPE assay; baculovirus coinfection; protein expression and purification; rational screening influenza A virus; CLK1 inhibitor; CPE assay; baculovirus coinfection; protein expression and purification; rational screening
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Zu, M.; Li, C.; Fang, J.-S.; Lian, W.-W.; Liu, A.-L.; Zheng, L.-S.; Du, G.-H. Drug Discovery of Host CLK1 Inhibitors for Influenza Treatment. Molecules 2015, 20, 19735-19747.

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