4-苯氧基苯氧乙基硫氰酸盐（WC-9）对恰加斯病病原体克氏锥虫的作用机制。
Mechanism of action of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the causative agent of Chagas' disease.
作者信息
Urbina Julio A, Concepcion Juan Luis, Montalvetti Andrea, Rodriguez Juan B, Docampo Roberto
机构信息
Laboratorio de Quimica Biológica, Centro de Bioquimica y Biofisica, Instituto Venezolano de Investigaciones Cientificas, Carretera Panamericana, Caracas 1020, Venezuela.
出版信息
Antimicrob Agents Chemother. 2003 Jun;47(6):2047-50. doi: 10.1128/AAC.47.6.2047-2050.2003.
Abstract
We investigated the molecular basis of the activity of 4-phenoxyphenoxyethyl thiocyanate (WC-9) against Trypanosoma cruzi, the etiological agent of Chagas' disease. We found that growth inhibition of T. cruzi epimastigotes induced by this compound was associated with a reduction in the content of the parasite's endogenous sterols due to a specific blockade of their de novo synthesis at the level of squalene synthase.
摘要
我们研究了4-苯氧基苯氧基乙基硫氰酸盐（WC-9）对恰加斯病的病原体克氏锥虫的活性分子基础。我们发现，该化合物诱导的克氏锥虫前鞭毛体生长抑制与寄生虫内源性固醇含量的降低有关，这是由于在角鲨烯合酶水平上对其从头合成的特异性阻断。
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本文引用的文献
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Mol Biochem Parasitol. 2002 Nov-Dec;125(1-2):35-45. doi: 10.1016/s0166-6851(02)00206-2.
2
Design, synthesis, and biological evaluation of aryloxyethyl thiocyanate derivatives against Trypanosoma cruzi.针对克氏锥虫的芳氧基乙基硫氰酸酯衍生物的设计、合成及生物学评价
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3
Recombinant squalene synthase. A mechanism for the rearrangement of presqualene diphosphate to squalene.重组鲨烯合酶。前鲨烯二磷酸重排为鲨烯的机制。
J Am Chem Soc. 2002 Jul 31;124(30):8846-53. doi: 10.1021/ja020411a.
4
Recombinant squalene synthase. Synthesis of non-head-to-tail isoprenoids in the absence of NADPH.重组鲨烯合酶。在无NADPH的情况下非头对头异戊二烯类化合物的合成。
J Am Chem Soc. 2002 Jul 31;124(30):8834-45. doi: 10.1021/ja020410i.
5
Specific treatment of Chagas disease: current status and new developments.恰加斯病的特异性治疗：现状与新进展
Curr Opin Infect Dis. 2001 Dec;14(6):733-41. doi: 10.1097/00001432-200112000-00012.
6
Chemotherapy of Chagas disease.恰加斯病的化疗
Curr Pharm Des. 2002;8(4):287-95. doi: 10.2174/1381612023396177.
7
Recent developments in the chemotherapy of Chagas disease.
Curr Pharm Des. 2001 Aug;7(12):1157-64. doi: 10.2174/1381612013397546.
8
Bisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase.双膦酸盐是克氏锥虫法尼基焦磷酸合酶的强效抑制剂。
J Biol Chem. 2001 Sep 7;276(36):33930-7. doi: 10.1074/jbc.M103950200. Epub 2001 Jul 2.
9
YM-53601, a novel squalene synthase inhibitor, reduces plasma cholesterol and triglyceride levels in several animal species.新型角鲨烯合酶抑制剂YM-53601可降低多种动物的血浆胆固醇和甘油三酯水平。
Br J Pharmacol. 2000 Sep;131(1):63-70. doi: 10.1038/sj.bjp.0703545.
10
Squalene synthase: steady-state, pre-steady-state, and isotope-trapping studies.角鲨烯合酶：稳态、预稳态及同位素捕获研究。
Biochemistry. 2000 Feb 22;39(7):1748-60. doi: 10.1021/bi9915014.
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