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Visible Light-Modulated Photoswitches for peptide stapling

用于肽装订的可见光调制光电开关

基本信息

批准号：
2468409
负责人：
金额：
--
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2468409
关键词：
Visible Light Modulated Photoswitches peptide

项目摘要

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.

第一年：针对CDT所有一年级学生的通用培训活动。2-4年级：由于其独特的大小和组成，肽类药物与以前在治疗领域占主导地位的小分子药物相比具有几个优势。它们是高度有效的，选择性的，并显示低水平的毒性和免疫原性。尽管有这些优点，但未修饰的肽通常以差的细胞膜渗透性和差的酶稳定性为特征，限制了它们在药物发现中的应用。已经开发了各种合成策略，包括肽钉合，以克服这些限制。肽钉合是一种大环化方法，在有或没有接头的帮助下，分子内连接两条肽侧链。使能够在用光照射时经历顺式-反式异构化的连接体变性形成光可切换肽。已报道含偶氮苯的钉合肽可改善肽螺旋度、细胞渗透性和生物活性。然而，所有报道的例子都需要使用皮肤损伤和弱皮肤穿透的UV光。本计画将发展一种新颖的双组份肽钉合方法，借由半胱氨酸结合将偶氮苯光开关并入未受保护的肽。为了合成简单起见，将进行与间，对-重氮苯的初始钉合。可见光调制邻氟偶氮苯的钉合将在未来尝试，以防止所需的使用紫外光。