Design of cyclic and d-amino acids containing peptidomimetics for inhibition of protein-protein interactions of HER2-HER3.
Design of cyclic and d-amino acids containing peptidomimetics for inhibition of protein-protein interactions of HER2-HER3.
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DOI：
10.1002/psc.3066
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Jois SD
中科院分区：
文献类型：
--
作者：
Pallerla S;Naik H;Singh S;Gauthier T;Sable R;Jois SD
HER2 受体是属于表皮生长因子受体家族 (EGFR) 的表面蛋白。它们在乳腺癌、肺癌和卵巢癌中的数量有所增加。 HER2阳性癌症具有侵袭性、死亡率较高且预后较差。我们设计了与 HER2 结合并阻断 HER2 介导的 EGFR 受体二聚化的肽模拟物。其中，一种对称的环状肽模拟物（化合物18）在HER2过表达的肺癌细胞系中表现出抗增殖活性，IC50值在纳摩尔浓度范围内。为了提高模拟肽的稳定性，在模拟肽中引入D-氨基酸，并设计了化合物18的几种类似物。在化合物18的类似物中，化合物32（一种环状的、含D-氨基酸的肽模拟物）被发现在HER2过表达的癌细胞系中具有纳摩尔范围内的IC50值。还使用模拟体内条件的 3D 细胞培养模型测量了化合物 32 的抗增殖活性。通过表面等离振子共振 (SPR) 研究化合物 32 与 HER2 蛋白的结合。体外稳定性研究表明，化合物32在血清中稳定48小时，并且在体内可检测到完整肽12小时。我们的研究结果表明，18 的 D-氨基酸类似物之一化合物 32 与 HER2 胞外结构域结合，抑制 HER2 激酶的磷酸化。
HER2 receptors are surface proteins belonging to the epidermal growth factor family of receptors (EGFR). Their numbers are elevated in breast, lung, and ovarian cancers. HER2-positive cancers are aggressive, higher mortality rate and have a poor prognosis. We have designed peptidomimetics that bind to HER2 and block the HER2-mediated dimerization of EGFR receptors. Among these, one symmetrical cyclic peptidomimetic (compound 18) exhibited antiproliferative activity in HER2-overexpressing lung cancer cell lines with an IC50 values in the nanomolar concentration range. To improve the stability of the peptidomimetic, D-amino acids were introduced into the peptidomimetic, and several analogs of compound 18 were designed. Among the analogs of compound 18, compound 32, a cyclic, D-amino acid-containing peptidomimetic, was found to have an IC50 value in the nanomolar range in HER2-overexpressing cancer cell lines. The anti-proliferative activity of compound 32 was also measured using a 3D cell culture model that mimics the in vivo conditions. The binding of compound 32 to the HER2 protein was studied by surface plasmon resonance (SPR). In vitro stability studies indicated that compound 32 was stable in serum for 48 h and intact peptide was detectable in vivo for 12 h. Results from our studies indicated that one of the D-amino acid analog of 18, compound 32 binds to the HER2 extracellular domain, inhibiting the phosphorylation of kinase of HER2.
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