Aza-peptidyl Michael acceptors.: A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens
Aza-peptidyl Michael acceptors.: A new class of potent and selective inhibitors of asparaginyl endopeptidases (legumains) from evolutionarily diverse pathogens
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DOI：
10.1021/jm701311r
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发表时间：
2008-05-08
影响因子：
7.3
通讯作者：
Powers, James C.
中科院分区：
文献类型：
--
作者：
Gotz, Marion G.;James, Karen Ellis;Powers, James C.
氮杂肽Michael受体是一类新型的天冬酰胺酰内肽酶（AE）抑制剂，其结构为Cbz-Ala-Ala-AAsn-trans-CH=CHCOR。一组31氮杂肽迈克尔受体的结构-活性关系（SAR）的特点与AE来自三个医学上重要的寄生虫：原生动物阴道毛滴虫，硬蜱蜱蓖麻，和扁虫血吸虫曼氏血吸虫。尽管这三种AE均由遗传学上不同的微生物引起，但它们的SAR非常相似，最低IC（50）值延伸至皮摩尔范围内。结果表明，活性位点的主要侧的地形上的进化约束。SAR还显示，在P1'位置的酯比二取代的酰胺更有效，并且单取代的酰胺和烷基衍生物显示很少或没有抑制。优选的P1'残基具有芳族取代基。氮杂-天冬酰胺基迈克尔受体与硫醇反应，这提供了深入了解其抑制天冬酰胺基内肽酶的机制。
Aza-peptide Michael acceptors with the general structure of Cbz-Ala-Ala-AAsn-trans-CH=CHCOR are a new class of inhibitors specific for the asparaginyl endopeptidases (AE) (legumains). Structure-activity relationships (SARs) were characterized for a set of 31 aza-peptide Michael acceptors with AEs derived from three medically important parasites: the protist Trichomonas vaginalis, the hard tick Ixodes ricinus, and the flatworm Schistosoma mansoni. Despite arising from phylogenetically disparate organisms, all three AEs shared a remarkably similar SAR with lowest IC(50) values extending into the picomolar range. The results suggest an evolutionary constraint on the topography of the prime side of the active site. SAR also revealed that esters in the P1' position are more potent than disubstituted amides and that monosubstituted arnides and alkyl derivatives show little or no inhibition. The preferred P1' residues have aromatic substituents. Aza-asparaginyl Michael acceptors react with thiols, which provides insight into the mechanism of their inhibition of asparaginyl endopeptidases.