High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis

doi:10.1186/s40249-015-0071-z

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	High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis
	Li, Ting 2; Ziniel, Peter D.1; He, Pan-qing 3; Kommer, Valerie P.1; Crowther, Gregory J.3; He, Min 2; Liu, Qing 2; Van Voorhis, Wesley C.3; Williams, David L.1; Wang, Ming-Wei2
刊名	INFECTIOUS DISEASES OF POVERTY
	2015-08-31
卷号	4
关键词	High-throughput screening Schistosomiasis Inhibitor Thioredoxin glutathione reductase
ISSN号	2049-9957
DOI	10.1186/s40249-015-0071-z
文献子类	Article
英文摘要	Background: Schistosomiasis, a parasitic disease also known as bilharzia and snail fever, is caused by different species of flatworms, such as Schistosoma mansoni (S. mansoni). Thioredoxin glutathione reductase (TGR) from S. mansoni (SmTGR) is a well-characterized drug target for schistosomiasis, yet no anti-SmTGR compounds have reached clinical trials, suggesting that therapeutic development against schistosomiasis might benefit from additional scaffolds targeting this enzyme. Methods: A high-throughput screening (HTS) assay in vitro against SmTGR was developed and applied to a diverse compound library. SmTGR activity was quantified with ThioGlo (R), a reagent that fluoresces upon binding to the free sulfhydryl groups of the reaction product GSH (reduced glutathione). Results: We implemented an HTS effort against 59,360 synthetic compounds. In the primary screening, initial hits (928 or 1.56 %) showing greater than 90 % inhibition on SmTGR activity at a final concentration of 10 mu M for each compound were identified. Further tests were carried out to confirm the effects of these hits and to explore the concentration-dependent response characteristics. As a result, 74 of them (0.12 %) representing 17 chemical scaffolds were confirmed and showed a great concentration-dependent inhibitory trend against SmTGR, including structures previously shown to be lethal to schistosomal growth. Of these, two scaffolds displayed a limited structure-activity relationship. When tested in cultured larvae, 39 compounds had cidal activity in 48 h, and five of them killed larvae completely at 3.125 mu M. Of these, three compounds also killed adult worms ex vivo at concentrations between 5 mu M and 10 mu M. Conclusion: These confirmed hits may serve as starting points for the development of novel therapeutics to combat schistosomiasis.
资助项目	World Health Organization's Special Programme for Research and Training in Tropical Diseases[WHO/TDR A80553] ; Ministry of Science and Technology of China[2014DFA31130] ; National Health and Family Planning Commission of China[2012ZX09304-011] ; National Health and Family Planning Commission of China[2013ZX09401003-005] ; National Health and Family Planning Commission of China[2013ZX09507-001] ; National Health and Family Planning Commission of China[2013ZX09507-002] ; Shanghai Science and Technology Development Fund[13DZ2290300] ; Shanghai Science and Technology Development Fund[15DZ2291600] ; Thousand Talents Program in China[00000000] ; NIAID[HHSN272201000005I]
WOS关键词	MANSONI ; PRAZIQUANTEL ; AFRICA
WOS研究方向	Infectious Diseases
语种	英语
出版者	BIOMED CENTRAL LTD
WOS记录号	WOS:000367171500002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276430]
专题	国家新药筛选中心
通讯作者	Wang, Ming-Wei
作者单位	1.Rush Univ, Med Ctr, Dept Immunol & Microbiol, Chicago, IL 60612 USA; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 3.Univ Washington, Div Allergy & Infect Dis, Seattle, WA 98195 USA
推荐引用方式 GB/T 7714	Li, Ting,Ziniel, Peter D.,He, Pan-qing,et al. High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis[J]. INFECTIOUS DISEASES OF POVERTY,2015,4.
APA	Li, Ting.,Ziniel, Peter D..,He, Pan-qing.,Kommer, Valerie P..,Crowther, Gregory J..,...&Wang, Ming-Wei.(2015).High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis.INFECTIOUS DISEASES OF POVERTY,4.
MLA	Li, Ting,et al."High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis".INFECTIOUS DISEASES OF POVERTY 4(2015).