Visible Light-Modulated Photoswitches for peptide stapling

第一年：为CDT所有一年级学生成员提供一般培训活动。第2-4年：由于其独特的大小和组成，肽基药物比以前主导治疗领域的小分子药物提供了几个优势。它们具有很强的效力、选择性和低水平的毒性和免疫原性。尽管有这些优点，未经修饰的肽通常具有细胞膜渗透性差和酶稳定性差的特点，限制了它们在药物发现中的应用。各种合成策略，包括肽钉接，已经发展克服这些限制。肽钉接是一种在分子内连接两个肽侧链的大环化方法，有或没有连接剂的帮助。结合一种能在光照射下进行顺式-反式异构化的连接体，形成光开关肽。含偶氮苯的钉接肽有改善肽螺旋度、细胞通透性和生物活性的报道。然而，所有报道的例子都需要使用皮肤损伤和弱皮肤穿透紫外线。该项目将开发一种新的双组分肽钉接方法，通过半胱氨酸偶联将偶氮苯光开关结合到无保护肽中。为简化合成，将采用m，对重偶氮苯进行初始钉接。然后，将来将尝试钉接可见光调制的邻氟偶氮苯，以防止所需的紫外线使用。

Year 1: Generic training activities for all first-year student members of the CDT.Year 2-4: Due to their unique size and composition, peptide-based drugs offer several advantages over small molecules which have previously dominated the therapeutic landscape. They are highly potent, selective and display low levels of toxicity and immunogenicity. Despite these advantages, unmodified peptides are often characterised by poor cell membrane permeability and poor enzymatic stability, limiting their application in drug discovery. Various synthetic strategies, including peptide stapling, have been developed to overcome these limitations. Peptide stapling is a method of macrocyclisation that intramolecularly links two peptide side chains, with and without the aid of a linker. Incorporating a linker, able to undergo cis-trans isomerisation upon irradiation with light, forms photoswitchable peptides. Azobenzene-containing stapled peptides have been reported to improve peptide helicity, cell permeability and biological activity. However, all examples reported require the use of skin-damaging and weakly skin-penetrating UV light. This project will develop a novel two component peptide stapling methodology for the incorporation of azobenzene photoswitches into unprotected peptides via cysteine conjugation. For the sake of synthetic simplicity, initial stapling with m,p- diazobenzene will be performed. The stapling of visible light modulated ortho-fluoroazobenzenes will then be attempted in the future, to prevent the required use of UV light.