2. Academic Validation
  3. Squalene synthase as a target for Chagas disease therapeutics

Squalene synthase as a target for Chagas disease therapeutics

  • PLoS Pathog. 2014 May 1;10(5):e1004114. doi: 10.1371/journal.ppat.1004114.
Na Shang 1,  Qian Li 2,  Tzu-Ping Ko 2,  Hsiu-Chien Chan 3,  Jikun Li 4,  Yingying Zheng 3,  Chun-Hsiang Huang 3,  Feifei Ren 3,  Chun-Chi Chen 3,  Zhen Zhu 3,  Melina Galizzi 5,  Zhu-Hong Li 5,  Carlos A Rodrigues-Poveda 6,  Dolores Gonzalez-Pacanowska 6,  Phercyles Veiga-Santos 7,  Tecia Maria Ulisses de Carvalho 7,  Wanderley de Souza 7,  Julio A Urbina 8,  Andrew H-J Wang 9,  Roberto Docampo 5,  Kai Li 10,  Yi-Liang Liu 10,  Eric Oldfield 11,  Rey-Ting Guo 3
Affiliations

Affiliations

  • 1 Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
  • 2 Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China; Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
  • 3 Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, China.
  • 4 Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
  • 5 Center for Tropical and Emerging Global Diseases and Department of Cellular Biology, University of Georgia, Athens, Georgia, United States of America.
  • 6 Instituto de Parasitología y Biomedicina "Lopez-Neyra", Consejo Superior de Investigaciones Cientificas, Granada, Spain.
  • 7 Laboratório de Ultraestrutura Celular Hertha Meyer, CCS, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, Brazil; Diretoria de Programa, Instituto Nacional de Metrologia, Normalização e Qualidade Industrial-INMETRO, Duque de Caxias, Rio de Janeiro, Brazil.
  • 8 Instituto Venezolano de Investigaciones Cientificas, Caracas, Venezuela.
  • 9 Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
  • 10 Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
  • 11 Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States of America.
PMID: 24789335 DOI: 10.1371/journal.ppat.1004114
Abstract

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.

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