An interdisciplinary pipeline for progressing cyclic peptides hits to small molecule inhibitors.

环肽被越来越多地用于发现具有挑战性的靶点，如蛋白质-蛋白质相互作用。环肽支架有几个优点，如抗蛋白水解性和主链环化提供的有限构象自由，从而产生与目标分子高度选择性和亲和力的分子。然而，尽管有这些优点，从环肽开发小分子药物仍然具有极大的挑战性。因此，需要新的方法来使环肽能够进展为类药物化合物并应用于临床。这个项目是阿里·塔瓦索利教授和乔纳森·埃塞克斯教授的实验室合作的。塔瓦索利实验室在发现和开发几种一流的环肽蛋白质-蛋白质相互作用抑制剂方面拥有专业知识。埃塞克斯实验室在开发和应用生物系统的计算机模拟方法方面经验丰富，特别强调蛋白质与配体的结合。该项目的化学生物学方面将涉及环肽抑制剂的合成和衍生化，并对这些分子进行各种生物物理分析，朝着合成和测试衍生小分子抑制剂的方向发展。这个项目的分子模拟部分将结合多种技术，包括基于配体和基于结构的技术，以识别、优化和衍生环多肽的小分子。该项目的多学科性质将为成功的申请者提供出色的培训。他们将受益于塔瓦索利和埃塞克斯实验室现有的专业知识，接受各种技术和学科的培训，并成为一系列实验和建模技术方面的专家，这一技能无疑将使学生在寻找未来工作方面处于非常有利的地位。

Cyclic peptides are increasingly used for hit discovery against challenging targets such as protein-protein interactions. There are several advantages to the cyclic peptide scaffold, such as resistance to proteolysis and limited conformational freedom conferred by backbone cyclization, which yields molecules that engage their targets with high selectivity and affinity. However, despite these advantages, the development of small molecule drugs from cyclic peptides remains extremely challenging. There is therefore a need for new approaches that enable the progression of cyclic peptides to drug-like compounds and toward the clinic.This project is a collaboration between the laboratories of Professor Ali Tavassoli and Professor Jonathan Essex. The Tavassoli lab have expertise in the discovery and development of several first in class cyclic peptide protein-protein interaction inhibitors. The Essex lab are experienced in the development and application of computer simulation methodology to biological systems, with a particular emphasis on protein-ligand binding. The chemical biology aspect of this project will involve the synthesis and derivatisation of cyclic peptide inhibitors and conducting a variety of biophysical assays on these molecules, moving towards synthesising and testing derived small molecule inhibitors. The molecular modelling component of this project will involve combining a number of techniques, both ligand-based and structure-based, to identify, optimise and derivatise cyclic peptides leads into small molecules.The multidisciplinary nature of the project will provide outstanding training for the successful applicant. They will benefit from the existing expertise of the Tavassoli and Essex laboratories, receiving training in a wide variety of techniques and disciplines, and becoming expert in a range of experimental and modelling techniques, a skillset that will undoubtedly leave the students very well placed in terms of finding future positions.