Aza-Peptidyl Michael Acceptor and Epoxide Inhibitors-Potent and Selective Inhibitors of Schistosoma mansoni and Ixodes ricinus Legumains (Asparaginyl Endopeptidases)
Aza-Peptidyl Michael Acceptor and Epoxide Inhibitors-Potent and Selective Inhibitors of Schistosoma mansoni and Ixodes ricinus Legumains (Asparaginyl Endopeptidases)
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DOI：
10.1021/jm900849h
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发表时间：
2009-11-26
影响因子：
7.3
通讯作者：
Powers, James C.
中科院分区：
文献类型：
--
作者：
Ovat, Asli;Muindi, Fanuel;Powers, James C.
氮杂肽Michael受体和环氧化物的一般结构分别为YCO-Ala-Ala-AAsn-trans-CH=CHCOR和YCO-Ala-Ala-AAsn-EP-COR，它们被证明是血吸虫、曼氏血吸虫（SmAE）和硬蜱、蓖麻硬蜱（IrAE）的天冬酰胺酰内肽酶（豆荚）的有效抑制剂。测定了一组41个氮杂肽Michael受体和8个氮杂肽环氧化物的构效关系（SAR）。这两种酶在P1'位置上更喜欢双取代的酰胺而不是单取代的酰胺，并且当我们增加该位置上抑制剂的疏水性时，效力增加。将抑制剂延伸至P5导致效力增加，特别是针对IrAE，并且两种酶在P2处都偏好小疏水残基而非大疏水残基。氮杂-肽迈克尔受体抑制剂比氮杂-肽环氧化物抑制剂更有效，并且对于这些化合物中的一些，二阶双光子速率常数是迄今发现的最快的。考虑到这些酶在两种寄生虫中的核心功能，本文提供的数据可能有助于选择性抗寄生虫药物的最终设计。
Aza-peptide Michael acceptors and epoxides with the general structure of YCO-Ala-Ala-AAsn-trans-CH=CHCOR and YCO-Ala-Ala-AAsn-EP-COR, respectively, are shown to be potent inhibitors of asparaginyl endopeptidases (legumains) from the bloodfluke, Schistosoma mansoni (SmAE), and the hard tick, Ixodes ricinus (IrAE). Structure-activity relationships (SARs) were determined for a set of 41 aza-peptide Michael acceptors and eight aza-peptide epoxides. Both enzymes prefer disubstituted amides to monosubstituted amides in the P1' position, and potency increased as we increased the hydrophobicity of the inhibitor in this position. Extending the inhibitor to P5 resulted in increased potency, especially against IrAE, and both enzymes prefer small over large hydrophobic residues at P2. Aza-peptide Michael acceptor inhibitors are more potent than aza-peptide epoxide inhibitors, and for some of these compounds, second-order inhibiton rate constants are the fastest yet discovered. Given the central functions of these enzymes in both parasites, the data presented here may facilitate the eventual design of selective antiparasitic drugs.