STRUCTURAL STUDIES OF A FAMILY OF HIGH-AFFINITY LIGANDS FOR GPIIB/IIIA
STRUCTURAL STUDIES OF A FAMILY OF HIGH-AFFINITY LIGANDS FOR GPIIB/IIIA
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DOI：
10.1021/ja00087a006
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发表时间：
1994-04-20
影响因子：
15
通讯作者：
DEGRADO, WF
中科院分区：
文献类型：
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作者：
BACH, AC;EYERMANN, CJ;DEGRADO, WF
通过在半刚性连接物间氨基甲基苯甲酸(MAMB)的两端连接一个含有RGD的四肽序列，合成了一类有效的糖蛋白IIb/IIIa黏附分子的口服活性环肽拮抗剂。为了确定这种氨基酸如何限制介导肽序列的构象，并阐明多肽的受体结合构象，我们研究了9个环状类似物的溶液和固体结构，它们的受体结合常数大约跨越4个数量级。这些类似物的总结构为环(xxx-Arg-Gly-Asp-Mamb)。每个化合物的主链构象都是以xxx-Arg键为中心的长方形。在本系列最有效的化合物中，xxx是一种小的脂肪族D-氨基酸，Arg残基的N-α是甲基化的：包含这些特征的多肽是高度刚性的，包含以D-Abu-N-MeArg二肽为中心的II‘型β转角，高度扩展的甘氨酸残基，以及以天冬氨酸为中心的C-7转角。缺少N-甲基和/或在xxx具有反手性的多肽更具弹性。N-α-甲基也限制了Arg侧链的构象。此外，D-氨基酸的脂肪族侧链、N-MeArg的N-α-甲基和MAMB接头的苯基形成了一个连续的疏水表面，这可能与受体作用良好。最后，研究了在MAMB和Asp残基引入的构象限制的影响，以确定它们对受体结合的影响。
A class of potent orally active cyclic peptide antagonists of the glycoprotein IIb/IIIa adhesion molecule have been prepared by linking a tetrapeptide, RGD-containing sequence between the two ends of a semirigid linker, m-(aminomethyl)benzoic acid (Mamb). To determine how this amino acid constrains the conformation of the intervening peptide sequence and to shed some light on the receptor-bound conformation of the peptide, we examined the solution and solid-state structures of nine cyclic analogues whose receptor binding constants span approximately 4 orders of magnitude. The general structure of these analogues is cyclo(Xxx-Arg-Gly-Asp-Mamb). The backbone conformations of each compound trace out a rectangular shape with a beta-turn centered at the Xxx-Arg bond. In the most potent compounds in this series Xxx is a small, aliphatic D-amino acid, and N-alpha of the Arg residue is methylated: peptides containing these features are highly rigid and contain a type II' beta-turn centered at the D-Abu-N-MeArg dipeptide, a highly extended Gly residue, and a C-7 turn centered at the Asp. Peptides lacking the N-methyl group and/or with reversed chirality at Xxx are more flexible. The N-alpha-methyl group also restricts the conformation of the Arg side chain. In addition the aliphatic side chain of the D-amino acid, the N-alpha-methyl of N-MeArg, and the phenyl group of the Mamb linker form a continuous hydrophobic surface, which presumably interacts favorably with the receptor. Finally, the effects of conformational constraints introduced at the Mamb and the Asp residues were investigated to determine their effects on receptor binding.