Verdine Gregory L, Hilinski Gerard J
Department of Chemistry and Chemical Biology, Harvard University, and Program in Cancer Chemical Biology, Dana - Farber Cancer Institute, Boston, Massachusetts, USA.
Methods Enzymol. 2012;503:3-33. doi: 10.1016/B978-0-12-396962-0.00001-X.
Proteins that engage in intracellular interactions with other proteins are widely considered among the most biologically appealing yet chemically intractable targets for drug discovery. The critical interaction surfaces of these proteins typically lack the deep hydrophobic involutions that enable potent, selective targeting by small organic molecules, and their localization within the cell puts them beyond the reach of protein therapeutics. Considerable interest has therefore arisen in next-generation targeting molecules that combine the broad target recognition capabilities of protein therapeutics with the robust cell-penetrating ability of small molecules. One type that has shown promise in early-stage studies is hydrocarbon-stapled α-helical peptides, a novel class of synthetic miniproteins locked into their bioactive α-helical fold through the site-specific introduction of a chemical brace, an all-hydrocarbon staple. Stapling can greatly improve the pharmacologic performance of peptides, increasing their target affinity, proteolytic resistance, and serum half-life while conferring on them high levels of cell penetration through endocytic vesicle trafficking. Here, we discuss considerations crucial to the successful design and evaluation of potent stapled peptide interactions, our intention being to facilitate the broad application of this technology to intractable targets of both basic biologic interest and potential therapeutic value.
与其他蛋白质进行细胞内相互作用的蛋白质，在药物研发中被广泛认为是最具生物学吸引力但化学性质难以处理的靶点之一。这些蛋白质的关键相互作用表面通常缺乏能使小分子实现强效、选择性靶向的深疏水内陷结构，而且它们在细胞内的定位使得蛋白质疗法难以触及。因此，人们对下一代靶向分子产生了浓厚兴趣，这类分子将蛋白质疗法广泛的靶点识别能力与小分子强大的细胞穿透能力结合起来。在早期研究中显示出前景的一种类型是碳氢化合物钉合的α - 螺旋肽，这是一类新型的合成小蛋白，通过位点特异性引入化学支架（一种全碳氢化合物钉）锁定在其生物活性α - 螺旋构象中。钉合可以极大地改善肽的药理性能，提高它们的靶点亲和力、抗蛋白水解能力和血清半衰期，同时通过内吞小泡运输赋予它们高水平的细胞穿透能力。在此，我们讨论对成功设计和评估强效钉合肽相互作用至关重要的考虑因素，目的是促进该技术在具有基础生物学意义和潜在治疗价值的难处理靶点上的广泛应用。
