Diversity-Oriented Synthesis of Stapled Peptides

制药业历来在开发针对酶和受体蛋白等靶标的疗法方面取得了巨大成功。近年来，人们看到了探索新的、更具挑战性的生物目标的转变。蛋白质-蛋白质相互作用(PPI)是新的潜在药物靶点的一个令人难以置信的丰富来源，因为它们与包括各种癌症在内的人类疾病有着无可辩驳的联系。不幸的是，PPI仍然是一大类未被充分利用的药物靶点，因为传统的小分子方法通常不能理想地抑制PPI界面。构象受限的多肽(通常被称为“装订多肽”)已经成为一种很有前途的策略，可以解决这些历史上“不可用药”的靶点，并为许多疾病的复杂机制提供新的有价值的见解，这些疾病具有高度未得到满足的医疗需求。这项提议旨在开发一个新的支持平台，用于高效生产各种构象受限的多肽，这些多肽具有与制药行业直接相关的量身定制的特性。这项技术将在其效率、适应性和实施简单性方面出类拔萃，并将代表着从目前的化学方法到获得具有特定化学/生物特征的限制性多肽的重大变化。拟议的工作有可能为快速发现和优化下一代癌症疗法定义一项一般战略，并为化学生物学研究提供大量新的高质量探针。

The pharmaceutical industry has historically had great success in developing therapeutics against targets such as enzymes and receptor proteins. Recent years have witnessed a shift towards exploring new and more challenging biological targets. Protein-protein interactions (PPIs) represent an incredibly rich source of new potential drug targets, as they are irrefutably linked to human diseases, including various cancers. Unfortunately, PPIs remain a large and underexploited class of drug-targets as traditional small molecule approaches are often not ideal for inhibiting PPI interfaces. Conformationally-constrained peptides (often referred to as 'stapled peptides') has emerged as a promising strategy to address these historically 'undruggable' targets and provide new and valuable insights into the complex mechanisms that underlie many diseases with high unmet medical needs. This proposal aims to develop a new enabling platform for the efficient production of diverse conformationally-constrained peptides with tailored properties that are directly relevant to the pharmaceutical industry. The technique will be exceptional in its efficiency, adaptability and simplicity of implementation, and would represent a major step-change from current chemistry approaches to access constrained peptides with specific chemical/biological profiles. The proposed work has the potential to define a general strategy for the rapid discovery and optimisation of next-generation cancer therapeutics, and deliver a vast array of new high-quality probes for chemical biology studies.