CEA (Commissariat à l'Energie Atomique), iBiTec-S, Service d'Ingénierie Moléculaire de Protéines (SIMOPRO), CE Saclay, 91191 Gif/Yvette, Cedex, France.
J Biol Chem. 2012 Aug 3;287(32):26647-56. doi: 10.1074/jbc.M112.380782. Epub 2012 Jun 11.
A series of pseudo-peptides with general formula X-l-Glu-NH(2) (with X corresponding to an acyl moiety with a long aryl-alkyl side chain) have been synthesized, evaluated as inhibitors of matrix metalloproteases (MMPs), and found to display remarkable nanomolar affinity. The loss in potency associated with a substitution of the P(2)' l-glutamate by a l-glutamine corroborates the importance of a carboxylate at this position. The binding mode of some of these inhibitors was characterized in solution and by x-ray crystallography in complex with various MMPs. The x-ray crystal structures reveal an unusual binding mode with the glutamate side chain chelating the active site zinc ion. Competition experiments between these inhibitors and acetohydroxamic acid, a small zinc-binding molecule, are in accord with the crystallographic results. One of these pseudo-dipeptides displays potency and selectivity toward MMP-12 similar to the best MMP-12 inhibitors reported to date. This novel family of pseudo peptides opens new opportunities to develop potent and selective inhibitors for several metzincins.
已合成了一系列通式为 X-l-Glu-NH(2) 的拟肽（其中 X 对应于具有长芳基-烷基侧链的酰基部分），并将其评估为基质金属蛋白酶（MMPs）的抑制剂，发现它们具有显著的纳摩尔亲和力。用 l-谷氨酰胺替代 P(2)'l-谷氨酸所导致的效力损失证实了该位置羧酸酯的重要性。这些抑制剂中的一些在溶液中和与各种 MMP 形成复合物的 X 射线晶体结构中进行了特征描述。X 射线晶体结构揭示了一种不寻常的结合模式，谷氨酸侧链螯合活性部位锌离子。这些抑制剂与乙二醛肟酸（一种小分子锌结合分子）之间的竞争实验与晶体学结果一致。这些拟二肽之一对 MMP-12 的效力和选择性与迄今为止报道的最佳 MMP-12 抑制剂相似。这种新型拟肽家族为开发几种金属蛋白酶的有效且选择性抑制剂提供了新的机会。
