a Institute for Molecular Bioscience , The University of Queensland , Brisbane , Australia.
Expert Opin Drug Discov. 2016 Dec;11(12):1151-1163. doi: 10.1080/17460441.2016.1245720. Epub 2016 Oct 16.
Macrocyclic peptides are generally more resistant to proteolysis and often have higher potency than linear peptides and so they are excellent leads in drug design. Their study is significant because they offer potential as a new generation of drugs that are potent and specific, and thus might have fewer side effects than traditional small molecule drugs. Areas covered: This article covers macrocyclic drug leads based on nature-derived cyclic peptides as well as synthetic cyclic peptides and close derivatives. The natural peptides include cyclotides, sunflower-derived peptides, theta-defensins and orbitides. Technologies to make engineered cyclic peptides covered here include cyclization via amino acid linkers, CLIPS, templates, and stapled peptides. Expert opinion: Macrocyclic peptides are promising drug leads and several are in clinical trials. The authors believe they offer key advantages over traditional small molecule drugs, as well as some advantages over protein-based 'biologics' such as antibodies or growth factors. These include the ability to penetrate cells and attack intracellular targets such as protein-protein interactions as well as to hit extracellular targets. Some macrocyclic peptides such as cyclotides offer the potential for production in plants, thus reducing manufacture costs and potentially increasing opportunities for their distribution to developing countries at low cost.
大环肽通常对蛋白水解更具抗性，并且往往比线性肽具有更高的效力，因此它们是药物设计的优秀先导物。它们的研究意义重大，因为它们有可能成为新一代的药物，具有高效和特异性，因此可能比传统的小分子药物副作用更少。涵盖领域：本文涵盖了基于天然衍生的环肽以及合成环肽和紧密衍生物的大环药物先导物。天然肽包括环肽、向日葵衍生肽、θ-防御素和轨道肽。这里涵盖的用于制造工程环肽的技术包括通过氨基酸接头、CLIPS、模板和订书肽进行环化。专家意见：大环肽是很有前途的药物先导物，其中一些正在临床试验中。作者认为，它们提供了优于传统小分子药物的关键优势，以及优于基于蛋白质的“生物制品”（如抗体或生长因子）的一些优势。这些优势包括穿透细胞和攻击细胞内靶点（如蛋白质-蛋白质相互作用）以及攻击细胞外靶点的能力。一些大环肽，如环肽，有可能在植物中生产，从而降低制造成本，并有可能以低成本向发展中国家提供更多的分销机会。
