Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity.
Vipegitide: a folded peptidomimetic partial antagonist of α2β1 integrin with antiplatelet aggregation activity.
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DOI：
10.2147/dddt.s72844
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Lazarovici P
中科院分区：
文献类型：
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作者：
Momic T;Katzhendler J;Shai E;Noy E;Senderowitz H;Eble JA;Marcinkiewicz C;Varon D;Lazarovici P
以含有WKTSRTSHY序列的线性肽为先导化合物，合成了一种具有血小板聚集抑制活性的α2β1整合素拟肽拮抗剂Vipegitide。Vipegitide是一种13个氨基酸的折叠肽模拟物分子，在6和8位含有两个α-氨基异丁酸残基，在人血清中不稳定。用两个聚乙二醇（PEG）分子的单元分别取代位置1和2处的甘氨酸和色氨酸残基，产生在人血清中稳定超过3小时的拟肽Vipegitide-PEG 2。Vipegitide和Vipegitide-PEG 2在抑制α1/α2整联蛋白过度表达细胞与相应胶原的粘附方面显示出高效力（分别为7×10−10 M和1.5×10−10 M）和中等效力（分别为40%和35%）以及对α2整联蛋白的选择性。在与重组α2 A-结构域的无细胞结合试验中证实了两种肽模拟物与α2整合素胞外活性结构域的相互作用。在血小板膜上发现整合素α2β1受体，并触发胶原诱导的血小板聚集。在流动条件下，Vipegitide和Vipegitide-PEG 2抑制α2β1整合素介导的人和鼠血小板粘附50%。他们有效地阻止腺苷二磷酸和胶原蛋白I诱导的血小板聚集在富含血小板的血浆和全血。Vipegitide-PEG 2的效力高于Vipegitide-PEG 2，这与水中分子的计算机建模结果一致。这些肽模拟物分子在静脉推注50 mg/kg后在小鼠中急性耐受。这些结果强调了Vipegitide和Vipegitide-PEG 2分子作为血小板聚集抑制药物先导化合物在抗血栓治疗中的效力。
Linear peptides containing the sequence WKTSRTSHY were used as lead compounds to synthesize a novel peptidomimetic antagonist of α2β1 integrin, with platelet aggregation-inhibiting activity, named Vipegitide. Vipegitide is a 13-amino acid, folded peptidomimetic molecule, containing two α-aminoisobutyric acid residues at positions 6 and 8 and not stable in human serum. Substitution of glycine and tryptophan residues at positions 1 and 2, respectively, with a unit of two polyethylene glycol (PEG) molecules yielded peptidomimetic Vipegitide-PEG2, stable in human serum for over 3 hours. Vipegitide and Vipegitide-PEG2 showed high potency (7×10−10 M and 1.5×10−10 M, respectively) and intermediate efficacy (40% and 35%, respectively) as well as selectivity toward α2 integrin in inhibition of adhesion of α1/α2 integrin overexpressing cells toward respective collagens. Interaction of both peptidomimetics with extracellular active domain of α2 integrin was confirmed in cell-free binding assay with recombinant α2 A-domain. Integrin α2β1 receptor is found on the platelet membrane and triggers collagen-induced platelet aggregation. Vipegitide and Vipegitide-PEG2 inhibited α2β1 integrin-mediated adhesion of human and murine platelets under the flow condition, by 50%. They efficiently blocked adenosine diphosphate- and collagen I-induced platelet aggregation in platelet rich plasma and whole human blood. Higher potency of Vipegitide than Vipegitide-PEG2 is consistent with results of computer modeling of the molecules in water. These peptidomimetic molecules were acutely tolerated in mice upon intravenous bolus injection of 50 mg/kg. These results underline the potency of Vipegitide and Vipegitide-PEG2 molecules as platelet aggregation-inhibiting drug lead compounds in antithrombotic therapy.