Synthesis and evaluation of aza-peptidyl inhibitors of the lysosomal asparaginyl endopeptidase, legumain.
Synthesis and evaluation of aza-peptidyl inhibitors of the lysosomal asparaginyl endopeptidase, legumain.
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DOI：
10.1016/j.bmcl.2011.12.079
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发表时间：
2012-02-01
影响因子：
2.7
通讯作者：
Bogyo, Matthew
中科院分区：
文献类型：
--
作者：
Lee, Jiyoun;Bogyo, Matthew
关键词：
Legumain 或天冬酰胺内肽酶 (AEP) 是一种溶酶体半胱氨酸蛋白酶，对天冬酰胺残基后的蛋白质底物裂解具有高度特异性。当处于溶酶体的酸性环境中时，它还能够在天冬氨酸位点后裂解。 Legumain 的表达和活性与许多病理状况有关，包括癌症、动脉粥样硬化和炎症，但其在这些病理中的生物学作用尚不清楚。高效且选择性的legumain抑制剂不仅对于研究legumain在这些疾病中的功能作用有价值，而且还可能具有治疗潜力。我们在此描述了基于氮杂天冬酰胺基支架的选择性legumain抑制剂的设计、合成和体外评价。我们合成了具有各种非天然氨基酸和不同亲电子弹头的氮杂肽基抑制剂文库，并表征了legumain失活的动力学特性。我们还合成了荧光标记的抑制剂来研究化合物的细胞渗透性和选择性。该抑制剂对重组小鼠legumain 的二阶速率常数高达 5×104 M−1s−1，IC50 值低至 4 nM。此外，该抑制剂对legumain具有高度选择性，并且与组织蛋白酶几乎没有或没有交叉反应性。总体而言，我们已经确定了几种有价值的新型legumain抑制剂，可用于研究多种疾病模型中legumain的功能。
Legumain or asparaginly endopeptidase (AEP) is a lysosomal cysteine protease with a high level of specificity for cleavage of protein substrates after an asparagine residue. It is also capable of cleaving after aspartic acids sites when in the acidic environment of the lysosome. Legumain expression and activity is linked to a number of pathological conditions including cancer, atherosclerosis and inflammation, yet its biological role in these pathologies is not well-understood. Highly potent and selective inhibitors of legumain would not only be valuable for studying the functional roles of legumain in these conditions, but may have therapeutic potential as well. We describe here the design, synthesis and in vitro evaluation of selective legumain inhibitors based on the aza-asparaginyl scaffold. We synthesized a library of aza-peptidyl inhibitors with various non-natural amino acids and different electrophilic warheads, and characterized the kinetic properties of inactivation of legumain. We also synthesized fluorescently labeled inhibitors to investigate cell permeability and selectivity of the compounds. The inhibitors have second order rate constants of up to 5×104 M−1s−1 and IC50 values as low as 4 nM against recombinant mouse legumain. In addition, the inhibitors are highly selective toward legumain and have little or no cross-reactivity with cathepsins. Overall, we have identified several valuable new inhibitors of legumain that can be used to study legumain function in multiple disease models.
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影响因子：
7.3
作者：
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通讯作者：
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发表时间：
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通讯作者：
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作者：
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通讯作者：
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