School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington 6012, New Zealand.
Centre for Biodiscovery, Victoria University of Wellington, Wellington 6012, New Zealand.
Mar Drugs. 2020 Jan 27;18(2):81. doi: 10.3390/md18020081.
The Hsp70/J-protein machinery plays an essential role in survival, differentiation, and pathogenesis of the protozoan parasite, and is an emerging target against African Trypanosomiasis. This study evaluated a set of small molecules, inspired by the malonganenones and nuttingins, as modulators of the chaperone activity of the cytosolic heat inducible T. brucei Hsp70 and constitutive TbHsp70.4 proteins. The compounds were assessed for cytotoxicity on both the bloodstream form of T. b. brucei parasites and a mammalian cell line. The compounds were then investigated for their modulatory effect on the aggregation suppression and ATPase activities of the TbHsp70 proteins. A structure-activity relationship for the malonganenone-class of alkaloids is proposed based upon these results.
Hsp70/J 蛋白机器在原生动物寄生虫的存活、分化和发病机制中起着至关重要的作用，是针对非洲锥虫病的新兴靶点。本研究评估了一组小分子，这些小分子的灵感来自于马拉戈南酮和努廷，作为细胞质热诱导的 T. brucei Hsp70 和组成型 TbHsp70.4 蛋白伴侣活性的调节剂。评估了这些化合物对锥虫 bloodstream 形式的 T. b. brucei 寄生虫和哺乳动物细胞系的细胞毒性。然后，研究了这些化合物对 TbHsp70 蛋白聚集抑制和 ATPase 活性的调节作用。根据这些结果，提出了马拉戈南酮类生物碱的结构-活性关系。
