Salvati Maria, Cordero Franca M, Pisaneschi Federica, Melani Fabrizio, Gratteri Paola, Cini Nicoletta, Bottoncetti Anna, Brandi Alberto
Department of Organic Chemistry Ugo Schiff University of Firenze via della Lastruccia 13, I-50019 Sesto Fiorentino (FI), Italy.
Bioorg Med Chem. 2008 Apr 15;16(8):4262-71. doi: 10.1016/j.bmc.2008.02.080. Epub 2008 Feb 29.
The solid-phase synthesis of two diastereomeric cyclic pseudopeptides containing the Arg-Gly-Asp sequence and the dipeptide isostere 2-amino-3-oxotetrahydro-1H-pyrrolizine-7a(5H)-carboxylic acid (GPTM) is described. Competition binding assays to purified alphavbeta3 and alphavbeta5 integrins with respect to [125I]echistatin showed a high inhibitory activity for the (2S,7aS)-GPTM derivative. Effects of the structural constraint induced by the two enantiomeric scaffolds (2R,7aR)-GPTM and (2S,7aS)-GPTM on the conformation of Arg-Gly-Asp sequence have been computationally investigated using as a reference the recently solved X-ray structure of cyclo(Arg-Gly-Asp-d-Phe-[N-Me]Val) in complex with the extracellular fragment of the alphavbeta3 receptor. The computational method disclosed the key role played by a bridging water molecule on differentiating the two ligands by a diverse stabilization of the ligand-protein complex.
本文描述了两种含有精氨酸-甘氨酸-天冬氨酸序列以及二肽类似物2-氨基-3-氧代四氢-1H-吡咯并[2,1-a]异喹啉-7a(5H)-羧酸（GPTM）的非对映体环状假肽的固相合成。针对纯化的αvβ3和αvβ5整合素，以[125I]echistatin为参照进行的竞争结合试验表明，(2S,7aS)-GPTM衍生物具有高抑制活性。以最近解析的与αvβ3受体细胞外片段复合的环（精氨酸-甘氨酸-天冬氨酸-d-苯丙氨酸-[N-甲基]缬氨酸）的X射线结构为参照，通过计算研究了两种对映体支架(2R,7aR)-GPTM和(2S,7aS)-GPTM诱导的结构限制对精氨酸-甘氨酸-天冬氨酸序列构象的影响。该计算方法揭示了一个桥连水分子通过对配体-蛋白质复合物的不同稳定作用在区分这两种配体中所起的关键作用。
