Covalent Warhead-Functionalised Cyclic Peptide Discovery

该项目涉及开发一个改进的基于mrna显示的平台（RaPID），以允许鉴定共价环肽。最初的共价半胱氨酸反应性弹头将被纳入快速肽库，使用遗传密码重编程和优化的选择方法，以识别PADI4的共价抑制剂，PADI4是一种在炎症疾病中经常失调的精氨酸去亚胺酶。随后，优化的选择方法将与实验室的努力相结合，将dna模板化的化学物质编码到RaPID文库中，允许将编码多个共价弹头的文库筛选到单个文库中，从而促进针对广泛目标的共价化学探针的发现，即使在容易配体残基未知的情况下。

This project involves developing a modified mRNA-display-based platform (RaPID) to allow identification covalent cyclic peptides. Initially covalent cysteine reactive warheads will be incorporated into RaPID peptide libraries using genetic code reprogramming and selection methodology optimised to allow identification of covalent inhibitors of PADI4, an arginine deiminases frequently misregulated in inflammatory diseases. Subsequently, the optimised selection methodology will be combined with efforts in the lab to encode DNA-templated chemistry into RaPID libraries allowing the screening of libraries encoding multiple covalent warheads into a single library, facilitating the discovery of covalent chemical probes against a wide range of targets, even where readily ligandable residues are unknown.