Design and evaluation of Trypanosoma brucei metacaspase inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

Berg, Maya¹  Van der Veken, Pieter¹  Joossens, Jurgen¹  Muthusamy, Venkatraj¹  Breugelmans, Matthias¹  Moss, Catherine X.^2,3  Rudolf, Jana^2,3  Cos, Paul⁴  Coombs, Graham H.⁵  Maes, Louis⁴  Haemers, Achiel¹  Mottram, Jeremy C.^2,3  Augustyns, Koen¹ 

[1] Univ Antwerp, Med Chem Lab, B-2610 Antwerp, Belgium

[2] Univ Glasgow, Fac Biomed & Life Sci, Glasgow G12 8TA, Lanark, Scotland

[3] Univ Glasgow, Wellcome Ctr Mol Parasitol, Glasgow G12 8TA, Lanark, Scotland

[4] Univ Antwerp, Lab Microbiol Parasitol & Hyg, Fac Pharmaceut Biomed & Vet Sci, B-2020 Antwerp, Belgium

[5] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, Glasgow G4 0NR, Lanark, Scotland

关键词: Trypanosoma brucei;    Metacaspase;    Inhibitor;    African trypanosomiasis;    Sleeping sickness;    Protease inhibitor;   

DOI  :  10.1016/j.bmcl.2010.01.099

来源: Elsevier

【 摘 要 】

Metacaspase (MCA) is an important enzyme in Trypanosoma brucei, absent from humans and differing significantly from the orthologous human caspases. Therefore MCA constitutes a new attractive drug target for antiparasitic chemotherapeutics, which needs further characterization to support the discovery of innovative drug candidates. A first series of inhibitors has been prepared on the basis of known substrate specificity and the predicted catalytic mechanism of the enzyme. In this Letter we present the first inhibitors of TbMCA2 with low micromolar enzymatic and antiparasitic activity in vitro combined with low cytotoxicity. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

Free