Diversity-Oriented Synthesis of Stapled Peptides

制药行业历来在开发针对酶和受体蛋白等靶标的治疗方法方面取得了巨大成功。近年来，人们开始转向探索新的、更具挑战性的生物靶点。蛋白质-蛋白质相互作用（PPIs）代表了一个令人难以置信的丰富的新的潜在药物靶点来源，因为它们与人类疾病，包括各种癌症无可辩驳地相关。不幸的是，由于传统的小分子方法通常不是抑制PPI界面的理想方法，PPI仍然是一个庞大且未被充分开发的药物靶点。构象约束肽（通常称为“钉状肽”）已成为解决这些历史上“不可药物”目标的有希望的策略，并为许多具有高度未满足医疗需求的疾病的复杂机制提供新的有价值的见解。该提案旨在开发一个新的支持平台，用于有效生产具有与制药行业直接相关的定制特性的各种构象约束肽。该技术将在其效率，适应性和简单性方面表现出色，并且将代表从当前化学方法到获得具有特定化学/生物特征的受限肽的重大转变。这项工作有可能为快速发现和优化下一代癌症治疗方法确定一个总体策略，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.