Squalene Synthase As a Target for Chagas Disease Therapeutics

Na Shang, Qian Li, Tzu Ping Ko, Hsiu Chien Chan, Jikun Li, Yingying Zheng, Chun Hsiang Huang, Feifei Ren, Chun Chi Chen, Zhen Zhu, Melina Galizzi, Zhu Hong Li, Carlos A. Rodrigues-Poveda, Dolores Gonzalez-Pacanowska, Phercyles Veiga-Santos, Tecia Maria Ulisses de Carvalho, Wanderley de Souza, Julio A. Urbina, Andrew H.J. Wang, Roberto DocampoKai Li, Yi Liang Liu, Eric Oldfield, Rey Ting Guo

研究成果: 雜誌貢獻文章同行評審

68 引文 斯高帕斯(Scopus)

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 anti-infective 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.

原文英語
文章編號e1004114
期刊PLoS Pathogens
10
發行號5
DOIs
出版狀態已發佈 - 5月 2014
對外發佈

ASJC Scopus subject areas

  • 寄生物學
  • 微生物學
  • 免疫學
  • 分子生物學
  • 遺傳學
  • 病毒學

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