Behar Anastasia E, Maayan Galia
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology Technion City, Haifa 3200008, Israel.
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology Technion City, Haifa 3200008, Israel.
J Inorg Biochem. 2025 Oct;271:112961. doi: 10.1016/j.jinorgbio.2025.112961. Epub 2025 May 28.
Peptoids (N-substituted glycine oligomers) represent an excellent platform for drug development, such as selective chelators for Cu ions towards chelation therapy, due to their efficient synthesis, high stability and good bioavailability. We previously showed that peptoids helicity is essential for selective Cu binding and identified a unique peptoid hexamer, having 2,2':6',2″-terpyridine, and 8-hydroxyquinoline as metal-binding sidechains facing the same side of the helix, which exhibits high selectivity to Cu ions. However, maintaining a stable helix required the incorporation of bulky chiral sidechains, resulting in a hydrophobic peptoid, insoluble in aqueous solutions, and limited in its use as a drug candidate. Our attempts to solubilize this peptoid led to the discovery of a water-soluble sequence able to selectively extract Cu from Cu-amyloid complex, and by this stop the formation of reactive oxygen species (ROS) in the context of Alzheimer's disease (AD). This peptoid, however, had limited solubility in buffer solutions (that mimic biological environment), thus its potential for further development as a therapeutic for AD was limited. In this current study, we explore the structure-function relationship within a newly synthesized set of helical and water-soluble peptoids. By extensive spectroscopic analysis we test the effect of helix stability as well as the type and number of the solubilizing group(s) and their position along the sequence, on the solubility of these peptoids in buffer, and on their selectivity for Cu and ability to inhibit ROS production. The results provide insights about the relationships between the structure of the peptoids/Cu-peptoids and ROS production inhibition.
类肽（N-取代甘氨酸低聚物）是药物开发的优良平台，例如作为铜离子的选择性螯合剂用于螯合疗法，这得益于其高效的合成、高稳定性和良好的生物利用度。我们之前表明类肽的螺旋结构对于选择性结合铜至关重要，并鉴定出一种独特的类肽六聚体，它具有2,2':6',2″-三联吡啶和8-羟基喹啉作为面向螺旋同一侧的金属结合侧链，对铜离子表现出高选择性。然而，维持稳定的螺旋结构需要引入庞大的手性侧链，这导致类肽具有疏水性，不溶于水溶液，限制了其作为候选药物的应用。我们使这种类肽溶解的尝试导致发现了一种水溶性序列，它能够从铜 - 淀粉样蛋白复合物中选择性提取铜，并由此在阿尔茨海默病（AD）的背景下阻止活性氧物种（ROS）的形成。然而，这种类肽在缓冲溶液（模拟生物环境）中的溶解度有限，因此其作为AD治疗药物进一步开发的潜力有限。在当前这项研究中，我们探索了一组新合成的螺旋状且水溶性类肽的结构 - 功能关系。通过广泛的光谱分析，我们测试了螺旋稳定性以及增溶基团的类型和数量及其在序列中的位置，对这些类肽在缓冲液中的溶解度、对铜的选择性以及抑制ROS产生能力的影响。结果提供了关于类肽/Cu-类肽结构与ROS产生抑制之间关系的见解。
