Polycyclic Peptide Therapeutics
Polycyclic Peptide Therapeutics
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DOI：
10.1002/cmdc.201200513
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发表时间：
2013-03-01
期刊：
影响因子：
3.4
通讯作者：
Heinis, Christian
中科院分区：
文献类型：
--
作者：
Baeriswyl, Vanessa;Heinis, Christian
由于其优异的结合特性、高稳定性和低脱靶毒性，多环肽是用于开发治疗剂的有吸引力的分子形式。目前，临床上仅使用少数多环肽;例子包括抗生素万古霉素、抗癌药物放线菌素D和罗米地辛以及镇痛药齐考诺肽。所有临床上使用的多环肽药物都来源于天然来源，如万古霉素、放线菌素D和罗米地辛的情况下的土壤细菌，或齐考诺肽的情况下的捕鱼螺旋蜗牛的毒液。不幸的是，大自然仅为一小部分治疗靶标提供肽大环配体。为了产生所选靶标的配体，研究人员使用合理设计或定向进化方法将人工结合位点插入天然多环肽支架，例如胱氨酸结蛋白。最近，已经从头产生了遗传编码的双环肽的大型组合文库，并通过噬菌体展示进行筛选。在这篇小综述中，讨论了现有的多环肽药物的性质，并与它们有趣的分子结构相关。此外，技术，允许非天然多环肽配体的发展进行了讨论。这些技术的最新应用已经产生了有希望的结果，表明多环肽疗法可能被开发用于广泛的疾病。
Owing to their excellent binding properties, high stability, and low off-target toxicity, polycyclic peptides are an attractive molecule format for the development of therapeutics. Currently, only a handful of polycyclic peptides are used in the clinic; examples include the antibiotic vancomycin, the anticancer drugs actinomycinD and romidepsin, and the analgesic agent ziconotide. All clinically used polycyclic peptide drugs are derived from natural sources, such as soil bacteria in the case of vancomycin, actinomycinD and romidepsin, or the venom of a fish-hunting coil snail in the case of ziconotide. Unfortunately, nature provides peptide macrocyclic ligands for only a small fraction of therapeutic targets. For the generation of ligands of targets of choice, researchers have inserted artificial binding sites into natural polycyclic peptide scaffolds, such as cystine knot proteins, using rational design or directed evolution approaches. More recently, large combinatorial libraries of genetically encoded bicyclic peptides have been generated denovo and screened by phage display. In this Minireview, the properties of existing polycyclic peptide drugs are discussed and related to their interesting molecular architectures. Furthermore, technologies that allow the development of unnatural polycyclic peptide ligands are discussed. Recent application of these technologies has generated promising results, suggesting that polycyclic peptide therapeutics could potentially be developed for a broad range of diseases.