Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

doi:10.1038/aps.2015.56

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	Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells
	Wu, Deng-wei 2; Mao, Fei 3; Ye, Yan 1; Li, Jian 3; Xu, Chuan-lian 2; Luo, Xiao-min1 ; Chen, Jing1 ; Shen, Xu1
刊名	ACTA PHARMACOLOGICA SINICA
	2015-09
卷号	36 期号:9 页码:1126-1136
关键词	Dengue virus antiviral drug NS2B/NS3 protease policresulen molecular docking molecular modeling
ISSN号	1671-4083
DOI	10.1038/aps.2015.56
文献子类	Article
英文摘要	Aim: Dengue is a severe epidemic disease caused by dengue virus (DENV) infection, for which no effective treatment is available. The protease complex, consisting of nonstructural protein 3 (NS3) and its cofactor NS2B, plays a pivotal role in the replication of DENV, thus may be a potential target for anti-DENV drugs. Here, we report a novel inhibitor of DENV2 NS2B/NS3 protease and its antiviral action. Methods: An enzymatic inhibition assay was used for screening DENV2 NS2B/NS3 inhibitors. Cytotoxicity to BHK-21 cells was assessed with MTT assay. Antiviral activity was evaluated in BHK-21 cells transfected with Rlu-DENV-Rep. The molecular mechanisms of the antiviral action was analyzed using surface plasmon resonance, ultraviolet-visible spectral analysis and differential scanning calorimetry assays, as well as molecular docking analysis combined with site-directed mutagenesis. Results: In our in-house library of old drugs (similar to 1000 compounds), a topical hemostatic and antiseptic 2-hydroxy-3,5-bis[(4-hydroxy-2-methyl-5-sulfophenyl) methyl]-4-methyl-benzene-sulfonic acid (policresulen) was found to be a potent inhibitor of DENV2 NS2B/NS3 protease with IC50 of 0.48 mu g/mL. Furthermore, policresulen inhibited DENV2 replication in BHK-21 cells with IC50 of 4.99 mu g/mL, whereas its IC50 for cytotoxicity to BHK-21 cells was 459.45 mu g/mL. Policresulen acted as a competitive inhibitor of the protease, and slightly affected the protease stability. Using biophysical technology-based assays and molecular docking analysis combined with site-directed mutagenesis, we demonstrated that the residues Gln106 and Arg133 of DENV2 NS2B/NS3 protease directly interacted with policresulen via hydrogen bonding. Conclusion: Policresulen is a potent inhibitor of DENV2 NS2B/NS3 protease that inhibits DENV2 replication in BHK-21 cells. The binding mode of the protease and policresulen provides useful hints for designing new type of inhibitors against the protease.
资助项目	National Natural Science Foundation of China[81220108025] ; National Natural Science Foundation of China[21222211] ; National Natural Science Foundation of China[81373461] ; National Natural Science Foundation of China[91413102] ; National Natural Science Foundation of China[81473141] ; National Natural Science Foundation of China[91213306]
WOS关键词	SMALL-MOLECULE INHIBITORS ; STRUCTURE-BASED DISCOVERY ; DRUG-LIKE MOLECULES ; DENGUE VIRUS ; SERINE-PROTEASE ; NS3 PROTEASE ; PEPTIDE INHIBITORS ; NS2B-NS3 PROTEASE ; ACCURATE DOCKING ; IN-VITRO
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5510639
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000360840200010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276417]
专题	药物安全性评价中心药物发现与设计中心
通讯作者	Xu, Chuan-lian
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Zhejiang, Peoples R China; 3.E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;
推荐引用方式 GB/T 7714	Wu, Deng-wei,Mao, Fei,Ye, Yan,et al. Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells[J]. ACTA PHARMACOLOGICA SINICA,2015,36(9):1126-1136.
APA	Wu, Deng-wei.,Mao, Fei.,Ye, Yan.,Li, Jian.,Xu, Chuan-lian.,...&Shen, Xu.(2015).Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells.ACTA PHARMACOLOGICA SINICA,36(9),1126-1136.
MLA	Wu, Deng-wei,et al."Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells".ACTA PHARMACOLOGICA SINICA 36.9(2015):1126-1136.