Trypanocidal effect of α′,β′-epoxyketones indicates that trypanosomes are particularly sensitive to inhibitors of proteasome trypsin-like activity
Trypanocidal effect of α′,β′-epoxyketones indicates that trypanosomes are particularly sensitive to inhibitors of proteasome trypsin-like activity
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DOI：
10.1016/j.ijantimicag.2004.02.023
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发表时间：
2004-09-01
影响因子：
10.8
通讯作者：
Steverding, D
中科院分区：
文献类型：
--
作者：
Glenn, RJ;Pemberton, AJ;Steverding, D
先前的研究表明，布氏锥虫蛋白酶体是非洲昏睡病新的化疗药物的候选者。在这项研究中，两个有效的和高选择性的α '，β'-环氧酮肽蛋白酶体抑制剂，环氧霉素和YU 101，已被测试了他们的锥虫杀锥虫活性，在体外培养适应的血液形式的布氏锥虫。这两种抑制剂显示出有希望的抗锥虫活性，ED 50和ED 90值在低至中等纳摩尔范围内。基于MIC值，环氧霉素表现出接近市售药物的选择性指数。蛋白酶体肽酶活性的酶分析表明，与哺乳动物细胞相比，锥虫是特别敏感的蛋白酶体的胰蛋白酶样活性的抑制。总之，这些数据表明，针对胰蛋白酶样活性的蛋白酶体抑制剂是未来抗锥虫药物开发的合理选择。(C)2004年，Elsevier B. V.和国际化疗学会。All rights reserved.
Previous studies have shown that the proteasome of Trypanosoma brucei is a candidate for novel chemotherapy of African sleeping sickness. In this study, two potent and highly selective alpha',beta'-epoxyketones peptide proteasome inhibitors, epoxomicin and YU101, have been tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of T brucei. Both inhibitors displayed promising anti-trypanosomal activities with ED50 and ED90 values in the low to mid nanomolar range. Based on MIC values, epoxomicin exhibited a selectivity index approaching those of commercially available drugs. Enzymatic analyses of proteasomal peptidase activities revealed that, compared with mammalian cells, trypanosomes are particular sensitive to inhibition of the trypsin-like activity of the proteasome. In conclusion, the data suggests that proteasome inhibitors targeting the trypsin-like activity are the rational choice for future anti-trypanosomal drug development. (C) 2004 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.