CYCLIC RGD PEPTIDE ANALOGS AS ANTIPLATELET ANTITHROMBOTICS
CYCLIC RGD PEPTIDE ANALOGS AS ANTIPLATELET ANTITHROMBOTICS
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DOI：
10.1021/jm00089a014
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发表时间：
1992-05-29
影响因子：
7.3
通讯作者：
BURNIER, JP
中科院分区：
文献类型：
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作者：
BARKER, PL;BULLENS, S;BURNIER, JP
血小板的刺激激活GPIIbIIIa（异二聚体整联蛋白受体）以结合纤维蛋白原（Fg），这导致血小板聚集。GPIIbIIIa/Fg结合抑制剂作为抗血栓剂潜在地适合于在溶栓治疗期间和之后的急性使用。将三肽序列Arg-Gly-Asp（RGD）（许多整联蛋白配体的共同结构元件）并入环肽中产生一系列具有一般结构BrAc-（AA 1）-RGD-Cys-OH的肽，其通过固相肽合成制备。通过N-末端溴乙酰基与半胱氨酸巯基在pH 8下以高稀释度反应完成环化，得到硫醚桥接的环肽[cyclo-S-Ac-（AA 1）-RGD-Cys-OH]。使用α-取代的溴乙酰基产生类似系列的乙酰基取代的硫醚桥接的环肽。硫醚的氧化产生可分离的非对映异构体亚砜桥接的环肽。在GPIIbIIIa ELISA试验和血小板聚集试验中进行全面评价后，选择G-4120（70 A; AA 1 = D-Tyr;亚砜桥）作为抗血栓形成剂进行进一步研究。G-4120在血小板聚集试验中与kistrin等效，kistrin是一种从蛇毒中分离的纤维蛋白原介导的血小板聚集的高效抑制剂（IC 50 = 0.15 μ M）。
Stimulation of platelets activates GPIIbIIIa, the heterodimeric integrin receptor, to bind fibrinogen (Fg), which results in platelet aggregation. GPIIbIIIa/Fg binding inhibitors are potentially suitable for acute use during and after thrombolytic therapy as antithrombotic agents. Incorporation of the tripeptide sequence Arg-Gly-Asp (RGD), a common structural element of many integrin ligands, into cyclic peptides produced a series of peptides of the general structure BrAc-(AA1)-RGD-Cys-OH, which were prepared by solid-phase peptide synthesis. Cyclization was accomplished by reaction of the N-terminal bromoacetyl group with the cysteine sulfhydryl at pH 8 at high dilution, resulting in thioether-bridged cyclic peptides [cyclo-S-Ac-(AA1)-RGD-Cys-OH]. Use of alpha-substituted bromoacetyl groups gave rise to an analogous series of acetyl-substituted thioether-bridged cyclic peptides. Oxidation of the thioethers produced separable diastereomeric sulfoxide-bridged cyclic peptides. After thorough evaluation in a GPIIbIIIa ELISA assay and a platelet aggregation assay, G-4120 (70A; AA1 = D-Tyr; sulfoxide bridge) was selected for further investigation as an antithrombotic agent. G-4120 was equipotent in the platelet aggregation assay to kistrin, a highly potent inhibitor of fibrinogen-mediated platelet aggregation isolated from snake venom (IC50 = 0.15-mu-M).