Covalent Warhead-Functionalised Cyclic Peptide Discovery

该项目包括开发一种改进的基于信使核糖核酸显示的平台(RAPID)，以便能够识别共价环肽。最初的共价半胱氨酸反应性弹头将被纳入快速多肽库，使用遗传密码重新编程和选择方法进行优化，以识别PADI4的共价抑制物，PADI4是一种在炎症性疾病中经常被错误调节的精氨酸脱亚胺酶。随后，优化的选择方法将与实验室将DNA模板化学编码到快速文库的努力结合起来，从而能够将编码多个共价弹头的文库筛选到一个文库中，从而促进发现针对广泛目标的共价化学探针，即使在容易连接的残基未知的情况下也是如此。

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.