Development of selective inhibitors and substrate of matrix metalloproteinase-12
Development of selective inhibitors and substrate of matrix metalloproteinase-12
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DOI：
10.1074/jbc.m600222200
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发表时间：
2006-04-21
影响因子：
4.8
通讯作者：
Dive, V
中科院分区：
文献类型：
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作者：
Devel, L;Rogakos, V;Dive, V
已制备了四个次膦酸肽文库，其中化合物具有通式 p-Br-Ph-(PO2-CH2)-Xaa'-Yaa'-Zaa'-NH2，并针对 10 种基质金属蛋白酶 (MMP) 进行了筛选。我们鉴定出两种次膦酸肽对 MMP-12（巨噬细胞弹性蛋白酶）的 K-i 值分别为 0.19 和 4.4 nM，这两种膦酸肽对其他测试的 MMP 的效力要低 2 - 3 个数量级以上。这些高度选择性的 MMP-12 抑制剂在其 Yaa'-Zaa' 位置含有 Glu-Glu 基序。将此 Glu-Glu 基序掺入由 MMP 切割的非特异性荧光肽的序列中，为 MMP-12 提供了高度选择性的底物。其中一种抑制剂与 MMP-12 相互作用的模型表明，观察到的选择性可能部分归因于 MMP-12 中存在两个独特的极性残基：Thr(239) 和 Lys(177)。这些 MMP-12 选择性抑制剂可能对 MMP-12 起关键作用的疾病具有重要的治疗应用，例如肺气肿、动脉粥样硬化和腹主动脉瘤。
Four phosphinic peptide libraries with compounds having the general formula p-Br-Ph-(PO2-CH2)-Xaa'-Yaa'-Zaa'-NH2 have been prepared and screened against 10 matrix metalloproteinases ( MMPs). We identified two phosphinic peptides with K-i values of 0.19 and 4.4 nM toward MMP-12 ( macrophage elastase) that are more than 2 - 3 orders of magnitude less potent toward the other MMPs tested. These highly selective MMP-12 inhibitors contain a Glu-Glu motif in their Yaa'-Zaa' positions. Incorporation of this Glu-Glu motif into the sequence of a nonspecific fluorogenic peptide cleaved by MMPs provides a highly selective substrate for MMP-12. A model of one of these inhibitors interacting with MMP-12 suggests that the selectivity observed might be due, in part, to the presence of two unique polar residues in MMP-12, Thr(239) and Lys(177). These MMP-12-selective inhibitors may have important therapeutic applications to diseases in which MMP-12 has been suggested to play a key role, such as in emphysema, atherosclerosis, and aortic abdominal aneurysm.