Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Bioorg Chem. 2021 Dec;117:105453. doi: 10.1016/j.bioorg.2021.105453. Epub 2021 Oct 26.
Human epidermal growth factor receptor 2 (HER2) has been recognized as an important therapeutic target for its overexpression in many cancers. Trastuzumab is a monoclonal antibody targeting HER2, which has been approved by FDA to treat HER2-positive cancer. In this research, cyclic peptide Cyclo-GCGPep1 was designed based on the binding mode between antibody and HER2 protein in silico, which has been confirmed possessing good affinity with HER2. Cyclo-GCGPep1 was also used to construct peptide-drug conjugates with Camptothecin. Biological evaluations demonstrated that Conjugate 1 has a good antiproliferative activity on SK-BR-3 and NCI-N87 cells. Conjugate 1 retained the pro-apoptotic and Topo I inhibitory ability of Camptothecin. Meanwhile, it has good targeting ability towards HER2-positive cells with the help of Cyclo-GCGPep1. It also has better permeability in the tumor spheroid model than Camptothecin. In summary, the design of cyclic peptide derived from antibody is of significance for the discovery of targeting peptides and Conjugate 1 is expected as a good therapeutic agent for HER2-positive cancers.
人表皮生长因子受体 2（HER2）在许多癌症中过表达，已被认为是一个重要的治疗靶点。曲妥珠单抗是一种针对 HER2 的单克隆抗体，已被 FDA 批准用于治疗 HER2 阳性癌症。在这项研究中，基于抗体与 HER2 蛋白结合模式的计算机模拟，设计了环肽 Cyclo-GCGPep1，已被证实与 HER2 具有良好的亲和力。Cyclo-GCGPep1 还被用于与喜树碱构建肽药物偶联物。生物学评价表明，偶联物 1 对 SK-BR-3 和 NCI-N87 细胞具有良好的增殖抑制活性。偶联物 1 保留了喜树碱的促凋亡和 Topo I 抑制能力。同时，在 Cyclo-GCGPep1 的帮助下，它对 HER2 阳性细胞具有良好的靶向能力。与喜树碱相比，它在肿瘤球体模型中的通透性也更好。总之，抗体衍生的环肽设计对于靶向肽的发现具有重要意义，偶联物 1 有望成为治疗 HER2 阳性癌症的良好治疗药物。
