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Insights into the molecular mechanisms of action of bioportides: a strategy to target protein-protein interactions
Expert Reviews in Molecular Medicine ( IF 4.5 ) Pub Date : 2015-01-27 , DOI: 10.1017/erm.2014.24
John Howl 1 , Sarah Jones 1
Affiliation  

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.

中文翻译:

深入了解生物载体的分子作用机制:一种针对蛋白质-蛋白质相互作用的策略

细胞穿透肽 (CPP) 是治疗药物靶向选择性细胞内递送的可靠载体。许多具有内在生物活性的 CPP(现在被称为 bioportides)的识别和应用进一步证明了 CPP 技术的巨大临床潜力。蛋白质模拟生物载体的改进,特别是模拟参与蛋白质-蛋白质相互作用 (PPI) 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,许多基于 CPP 的构建体目前正在作为人类治疗剂进行临床试验,特别关注抗癌剂。一系列特征明确的合成修饰,与现代固相合成兼容,可用于改善生物载体的生物物理和药理特性,从而实现体内细胞和组织的选择性靶向。此外,考虑到最近成功开发的钉合 α-螺旋肽作为抗癌剂,我们假设类似的结构修饰适用于设计更有效地调节已知是人类疾病基础的许多相互作用组的生物载体。因此,我们建议钉合螺旋生物端口可以满足代谢稳定、本质上具有细胞渗透性的药物的所有临床要求,这些药物能够通过具有最小毒性的显性负作用模式调节离散的 PPI。考虑到最近成功开发的钉合 α-螺旋肽作为抗癌剂,我们假设类似的结构修饰适用于设计更有效地调节已知是人类疾病基础的许多相互作用组的生物载体。因此,我们建议钉合螺旋生物端口可以满足代谢稳定、本质上具有细胞渗透性的药物的所有临床要求,这些药物能够通过具有最小毒性的显性负作用模式调节离散的 PPI。考虑到最近成功开发的钉合α-螺旋肽作为抗癌剂,我们假设类似的结构修饰适用于设计更有效地调节已知是人类疾病基础的许多相互作用组的生物载体。因此,我们建议钉合螺旋生物端口可以满足代谢稳定、本质上具有细胞渗透性的药物的所有临床要求,这些药物能够通过具有最小毒性的显性负作用模式调节离散的 PPI。
更新日期:2015-01-27
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