多肽合成

近日从南开大学获悉，该校元素有机化学国家重点实验室陈弓教授课题组开发了一种强力环状多肽化合物的化学合成方法，让困扰化学界多年的“高难度多肽成环”反应实现了高效、可控。作为环肽类分子合成化学领域的重要突破，该研究还为药物多肽开发提供了一种新颖的设计“工具”。相关研究成果发表在最新一期《自然·化学》上。

　　据介绍，与传统的小分子化合物相比，由多种氨基酸单元串联而成的多肽类化合物在构建体积更大的分子构架上有着独特的优势和潜力，已知的环肽类化合物具有包括抗肿瘤、抗HIV、抗菌、抗疟、安眠、抑制血小板聚集、免疫抑制等多方面的生物活性。既有研究表明，让链状的多肽“成环”可以在结构坚固性、细胞跨膜性、代谢稳定性等多个方面显著提高多肽的成药性。尽管在过去的几十年里，环肽的合成化学已有了长足的发展，但仍有很大局限，如何让这些“大个头”的多肽分子“定形”为理想的三维结构(环肽)并具有良好的药理性质还有着巨大的挑战。

　　受环肽天然产物生物合成的启发，陈弓团队通过金属催化对链状多肽底物上原本非常惰性的烷基碳氢键进行选择性活化，并和带有碘取代的芳香氨基酸侧链进行分子内偶联从而生成了各种环状产物。该方法把钯催化烷基碳氢键的活化反应巧妙地运用在复杂多肽的合成中，能“驯服”很多难以成环的链状多肽前体，让它们“乖乖”地关环。由于该方法采用了非常规的“碳氢键活化”合成策略，方法简洁、高效，底物适用范围广，不仅克服了长期困扰“多肽成环”反应的底物依赖性，还可高效制备了具有独特“苯环支撑架”结构的三维环肽骨架，为构建体积各异的环肽化合物提供了一条崭新的通用途径，也为发现更多具有良好先导药物活性新型环肽化合物，推动靶向多肽药物研发打下了坚实基础。

Recently learned from Nankai University, Professor Chen Gong of the State Key Laboratory for organic chemistry has developed a chemical synthesis of a powerful cyclic polypeptide compound, which has made the "highly difficult peptide ring" reaction in the chemical industry more efficient and controllable. As an important breakthrough in the field of synthetic chemistry of cyclic peptides, the study also provides a novel design tool for the development of polypeptide drugs. Relevant research results are published in the latest issue of nature chemistry.

It is said that, compared with the traditional small molecule compounds, the polypeptide compound, which is made up of a variety of amino acid units, has unique advantages and potential in the construction of a larger molecular structure. The known cyclo peptides include anti-tumor, anti HIV, antiseptic, antimalarial, hypnotic, inhibition of platelet aggregation and immunity. Inhibition of many aspects of biological activity. Previous studies have shown that the chain like polypeptide "ring" can significantly improve the polypeptide drug resistance in many aspects, such as structural strength, cell transmembrane, metabolic stability and so on. Although the synthetic chemistry of cyclin has made great progress over the past few decades, it still has great limitations. How to make these "big" peptide molecules "shape" as ideal three-dimensional structure (ring peptide) and have good pharmacological properties still have great challenges.

Inspired by the biosynthesis of natural products of cyclic peptides, the Chen bow team selectively activates the originally very inert alkyl hydrocarbon bonds on the chain polypeptide substrates by metal catalysis, and produces intramolecular coupling with the aromatic amino acid side chains with iodine substituted amino acids to produce various annular products. The method uses palladium to catalyze the activation of alkyl hydrocarbon bonds in the synthesis of complex peptides, which can "tame" many chain polypeptide precursors that are difficult to ring, so that they are "good" to close the ring. Because of the unconventional "hydrocarbon activation" synthesis strategy, the method is simple, efficient, and has a wide range of substrates. It not only overcomes the substrate dependence that perplex the "polypeptide ring" reaction for a long time, but also produces a three-dimensional cycP skeleton with a unique "benzene ring support frame" structure, which is for the construction of different volumes. The cyclic peptide compounds provide a new general approach, and also provide a solid foundation for the discovery of more good lead drug activity novel cyclic peptide compounds and the development of targeted peptide drugs.