Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
ChemMedChem. 2013 Mar;8(3):377-84. doi: 10.1002/cmdc.201200513. Epub 2013 Jan 25.
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 actinomycin D 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, actinomycin D 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 de novo 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.
由于其出色的结合特性、高稳定性和低脱靶毒性，多环肽是开发治疗药物的一种有吸引力的分子形式。目前，临床上仅使用少数几种多环肽；例如抗生素万古霉素、抗癌药物放线菌素 D 和罗米地辛以及镇痛药齐考诺肽。所有临床使用的多环肽药物均源自天然来源，例如万古霉素、放线菌素 D 和罗米地辛来自土壤细菌，齐考诺肽来自一种捕鱼的线纹芋螺的毒液。不幸的是，自然界只为一小部分治疗靶点提供肽大环配体。为了生成所选靶点的配体，研究人员使用合理设计或定向进化方法，在天然多环肽支架（如半胱氨酸结蛋白）中插入人工结合位点。最近，通过噬菌体展示，大规模组合文库的基因编码双环肽被从头生成并进行筛选。在这篇综述中，讨论了现有多环肽药物的特性，并将其与它们有趣的分子结构相关联。此外，还讨论了允许开发非天然多环肽配体的技术。这些技术的最新应用取得了有希望的结果，表明多环肽治疗药物可能有潜力针对广泛的疾病进行开发。
