环肽的固相环合策略研究进展

Research Progress on Solid-Phase Cyclization Strategies of Cyclized Peptides

环肽作为自然界存在的活性分子不仅具有显著的生物功能,还具有良好的成药性如蛋白酶水解稳定性、靶向选择性、细胞膜通透性和较高的生物利用度。这些优点使得环肽在疾病治疗和诊断领域展示出了十分广阔的应用前景。目前,已有40多种环肽药物应用于糖尿病、肿瘤、细菌感染等疾病的治疗。为了推动环肽的临床前研究,环肽及其衍生物的制备成为一个必须解决的问题。固相环合策略是一种直接在树脂上进行多肽环合的重要合成策略。它具有合成步骤简单、易于纯化、便于自动化操作能效避免液相环合时分子间副反应的优势。文章综述了均环肽和杂环肽在固相环化方面的最新进展,希望为今后不同类型环肽的合成提供有效参考策略。

Peptide drugs have become one of the most popular drug research and development targets in recent years due to their specific targeting,low toxicity,high efficacy,high selectivity and many other advantages.With the increasing difficulty of research and development of small molecule chemical drugs and the maturity of peptide solid-phase synthesis technology,researchers pay more and more attention to peptide drugs.So far,hundreds of peptide drugs have been approved in the United States,Europe and other regions.In 2019,the total sales of peptide drugs in the global market have reached US$44 billion,and its compound growth rate in recent seven years is higher than the average growth level of the global pharmaceutical industry,reaching 8.9%.As an important branch of peptide drugs,cyclopeptides reduce the degree of freedom of the parent conformation by forming a ring structure,thus prolonging its half-life in vivo and enhancing its stability to proteolytic enzymes.These unique advantages make cyclopeptides receive more and more attention in drug research and biomedical research.Cyclized peptides,as active molecules in nature,have not only significant biological functions,but also good druggability such as protease hydrolysis stability,targeting selectivity,cell membrane permeability and high bioavailability.These advantages make cyclized peptides show a very broad application prospect in the field of disease treatment and diagnosis.At present,more than 40 cyclic peptide drugs have been used in the treatment of diabetes,tumors,bacterial infections and other diseases.In order to promote the preclinical research of cyclic peptides,the preparation of cyclizd peptides and their derivatives had become a problem that must be solved.The solid-phase cyclization strategy was an important synthetic strategy for peptide cyclization directly on the resin.It had the advantages of simple synthesis steps,easy purification,convenient automatic operation and efficiency to avoid intermolecular side reactions during liquid phase cyclization.Herein,the recent advances in solidphase cyclization of homocyclic peptides and heterocyclic peptides were reviewed,hoping to provide an effective reference for the synthesis of different types of cyclic peptides in the future.