Molecular Pharmacology Group,Research Institute in Healthcare Science, University of Wolverhampton,Wulfruna Street,Wolverhampton WV1 1LY,UK.
Expert Rev Mol Med. 2015 Jan 27;17:e1. doi: 10.1017/erm.2014.24.
Cell-penetrating peptides (CPPs) are reliable vehicles for the target-selective intracellular delivery of therapeutic agents. The identification and application of numerous intrinsically bioactive CPPs, now designated as bioportides, is further endorsement of the tremendous clinical potential of CPP technologies. The refinement of proteomimetic bioportides, particularly sequences that mimic cationic α-helical domains involved in protein-protein interactions (PPIs), provides tremendous opportunities to modulate this emergent drug modality in a clinical setting. Thus, a number of CPP-based constructs are currently undergoing clinical trials as human therapeutics, with a particular focus upon anti-cancer agents. A well-characterised array of synthetic modifications, compatible with modern solid-phase synthesis, can be utilised to improve the biophysical and pharmacological properties of bioportides and so achieve cell-and tissue-selective targeting in vivo. Moreover, considering the recent successful development of stapled α-helical peptides as anti-cancer agents, we hypothesise that similar structural modifications are applicable to the design of bioportides that more effectively modulate the many interactomes known to underlie human diseases. Thus, we propose that stapled-helical bioportides could satisfy all of the clinical requirements for metabolically stable, intrinsically cell-permeable agents capable of regulating discrete PPIs by a dominant negative mode of action with minimal toxicity.
细胞穿透肽（CPPs）是一种可靠的载体，可将治疗剂靶向选择性递送至细胞内。大量具有内在生物活性的 CPPs 的鉴定和应用，现在被指定为生物肽，进一步证明了 CPP 技术具有巨大的临床潜力。拟肽生物肽的改进，特别是模拟涉及蛋白质-蛋白质相互作用（PPIs）的阳离子α-螺旋结构域的序列，为在临床环境中调节这种新兴药物模式提供了巨大的机会。因此，目前有许多基于 CPP 的构建体正在作为人类治疗剂进行临床试验，特别关注抗癌药物。一系列经过良好表征的合成修饰，与现代固相合成兼容，可以用于改善生物肽的物理化学和药理学性质，从而实现体内细胞和组织的选择性靶向。此外，考虑到最近作为抗癌药物的订书肽的成功开发，我们假设类似的结构修饰可应用于设计更有效地调节许多已知与人类疾病相关的相互作用组的生物肽。因此，我们提出，订书肽生物肽可以满足所有临床要求，即具有代谢稳定性、内在细胞通透性的药物，能够通过显性负作用模式调节离散的 PPI，具有最小的毒性。
