Squalene Synthase As a Target for Chagas Disease Therapeutics
文献类型：期刊论文
| 作者 | Shang, Na1,2; Li, Qian1,2; Ko, Tzu-Ping1,2; Chan, Hsiu-Chien1; Li, Jikun3; Zheng, Yingying1; Huang, Chun-Hsiang1; Ren, Feifei1; Chen, Chun-Chi1; Zhu, Zhen1 |
| 刊名 | PLOS PATHOGENS
 |
| 出版日期 | 2014-05-01 |
| 卷号 | 10期号:5 |
| 英文摘要 | Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel antiinfective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease. |
| WOS标题词 | Science & Technology ; Life Sciences & Biomedicine |
| 类目[WOS] | Microbiology ; Parasitology ; Virology |
| 研究领域[WOS] | Microbiology ; Parasitology ; Virology |
| 关键词[WOS] | NITROGEN-CONTAINING BISPHOSPHONATES ; FARNESYL DIPHOSPHATE SYNTHASE ; TRYPANOSOMA-CRUZI ; CHOLESTEROL-BIOSYNTHESIS ; ISOPRENOID BIOSYNTHESIS ; IN-VITRO ; MECHANISM ; INHIBITORS ; MODEL ; CRYSTALLOGRAPHY |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000337732300030 |
| 公开日期 | 2014-12-23 |
| 源URL | [http://124.16.173.210/handle/311007/540]  |
| 专题 | 天津工业生物技术研究所_结构生物学与蛋白酶学实验室 郭瑞庭_期刊论文 |
| 作者单位 | 1.Chinese Acad Sci, Tianjin Inst Ind Biotechnol, Ind Enzymes Natl Engn Lab, Tianjin, Peoples R China 2.Acad Sinica, Inst Biol Chem, Taipei, Taiwan 3.Univ Illinois, Ctr Biophys & Computat Biol, Urbana, IL USA 4.Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA 5.Univ Georgia, Dept Cellular Biol, Athens, GA 30602 USA 6.CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada, Spain 7.Univ Fed Rio de Janeiro, Lab Ultraestrutura Celular Hertha Meyer, Inst Biofis Carlos Chagas Filho, CCS, Rio De Janeiro, Brazil 8.Univ Fed Rio de Janeiro, Inst Nacl Ciencia & Tecnol Biol Estrutural & Bioi, Rio De Janeiro, Brazil 9.Inst Nacl Metrol Normalizacao & Qualidade Ind INM, Diretoria Programa, Rio De Janeiro, Brazil 10.Inst Venezolano Invest Cient, Caracas, Venezuela |
| 推荐引用方式 GB/T 7714 | Shang, Na,Li, Qian,Ko, Tzu-Ping,et al. Squalene Synthase As a Target for Chagas Disease Therapeutics[J]. PLOS PATHOGENS,2014,10(5). |
| APA | Shang, Na.,Li, Qian.,Ko, Tzu-Ping.,Chan, Hsiu-Chien.,Li, Jikun.,...&Guo, Rey-Ting.(2014).Squalene Synthase As a Target for Chagas Disease Therapeutics.PLOS PATHOGENS,10(5). |
| MLA | Shang, Na,et al."Squalene Synthase As a Target for Chagas Disease Therapeutics".PLOS PATHOGENS 10.5(2014). |
入库方式： OAI收割
来源：天津工业生物技术研究所
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