School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University , Shenzhen 518055, China.
Shenzhen Key Lab of Tissue Engineering, The Second People's Hospital of Shenzhen , Shenzhen 518035, China.
J Med Chem. 2017 Nov 9;60(21):8731-8740. doi: 10.1021/acs.jmedchem.7b00732. Epub 2017 Oct 31.
Direct inhibition of the protein-protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6 could potently inhibit cellular ERα's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein-protein interactions involved in a range of disorders.
直接抑制 ERα 与其内源性共激活因子的蛋白质-蛋白质相互作用，使用一种细胞渗透性稳定肽，可能为治疗 ERα 阳性乳腺癌提供一种新颖、有前途的策略。在这里，我们报告了一种由 N 端非天然交联天冬氨酸（TD）稳定的螺旋肽与 ERα 配体结合域（LBD）复合物的共晶结构。我们设计了一系列肽，其中肽 6 表现出与 ERα 的直接和高亲和力结合，并在 ERα 阳性乳腺癌细胞中具有选择性的抗增殖活性。TD 稳定的肽 6 与 ERα LBD 的共晶结构进一步表明，它形成一个α螺旋构象，并直接结合在 ERα 的共激活因子结合位点上。进一步的研究表明，肽 6 可以有效地抑制细胞内 ERα 的转录活性。这种方法证明了 TD 稳定肽在调节各种涉及多种疾病的细胞内蛋白质-蛋白质相互作用方面的潜力。
