High-throughput screening against thioredoxin glutathione reductase identifies novel inhibitors with potential therapeutic value for schistosomiasis
文献类型：期刊论文
| 作者 | Li, Ting2; Ziniel, Peter D.1; He, Pan-qing3; Kommer, Valerie P.1; Crowther, Gregory J.3; He, Min2; Liu, Qing2; Van Voorhis, Wesley C.3; Williams, David L.1; Wang, Ming-Wei2
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| 刊名 | INFECTIOUS DISEASES OF POVERTY
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| 出版日期 | 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. |
| WOS关键词 | MANSONI ; PRAZIQUANTEL ; AFRICA |
| 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研究方向 | Infectious Diseases |
| 语种 | 英语 |
| WOS记录号 | WOS:000367171500002 |
| 出版者 | BIOMED CENTRAL LTD |
| 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). |
入库方式： OAI收割
来源：上海药物研究所
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