Iaculli Debora, Montgomery Jade, Lamouroux Arthur, Caufriez Anne, Gozalbes Rafael, Vinken Mathieu, Molica Filippo, Kwak Brenda R, Ballet Steven
Research Group of Organic Chemistry, Departments of Bioengineering Sciences and Chemistry, Vrije Universiteit Brussel Brussels Belgium
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva Geneva Switzerland.
RSC Med Chem. 2024 Dec 21;16(3):1289-1303. doi: 10.1039/d4md00850b. eCollection 2025 Mar 19.
A peptide segment that is 10 residues long at the C-terminal (CT) region of Cx43 is known to be involved in interactions, both with the Cx43 protein itself and with other proteins, that result in hemichannel (HC) activity regulation. Previously reported mimetic peptides based on this region (, , ) have been revealed to be promising therapeutic agents in the context of cardiovascular diseases. In this work, novel approaches, such as C- and N-terminal modification and cyclization, to improve the proteolytic stability and bioavailability of the peptide are presented. These efforts resulted in a set of unprecedented potent cyclic inhibitors of HC-mediated ATP release with a half-life largely exceeding 24 hours. Additionally, the introduction of a lipophilic moiety with different solubilizing linkers led to the generation of a novel series of water-soluble and lipidated peptides that exhibited high inhibitory capacity in assays at submicromolar concentrations. A cardiac endothelium targeting strategy was also adopted, exploiting the ability of the CRPPR peptide to selectively deliver the peptides to endothelial cells.
已知连接蛋白43（Cx43）C端（CT）区域一个10个残基长的肽段参与Cx43蛋白自身以及与其他蛋白之间的相互作用，这些相互作用会导致半通道（HC）活性的调节。先前报道的基于该区域的模拟肽（……）已被证明在心血管疾病背景下是有前景的治疗药物。在这项工作中，提出了诸如C端和N端修饰以及环化等新方法，以提高该肽的蛋白水解稳定性和生物利用度。这些努力产生了一组前所未有的强效HC介导的ATP释放环化抑制剂，其半衰期大大超过24小时。此外，引入带有不同增溶连接子的亲脂性部分导致产生了一系列新型的水溶性和脂化肽，这些肽在亚微摩尔浓度的实验中表现出高抑制能力。还采用了心脏内皮靶向策略，利用CRPPR肽将这些肽选择性递送至内皮细胞的能力。
