订书肽的合成与应用

Chemical Synthesis and Applications of Stapled Peptides

许多重要的生物过程的调节都通过蛋白-蛋白相互作用来实现的。一般,蛋白-蛋白作用的界面太大而不能被小分子药物选择性靶向,因此小分子药物很难高效特异性地阻断该类型的相互作用。此外,由于蛋白质药物很难透过细胞膜,它们也不能直接靶向细胞内的相互作用。由于当前药物分子的限制,发展下一代既能进入细胞膜又能特异性靶向蛋白-蛋白相互作用的分子成为新的研究热点。为了克服上述药物分子的缺点,Verdine等发展了一种全碳支架的具有α-螺旋结构的新型多肽,这种多肽被称作订书肽(stapled peptides)。相比于天然多肽,订书肽有更高的酶解稳定性并且可以进入细胞膜,从而提高了它的药理性能。本文将从订书肽的化学合成、生物物理性能的表征和其在癌症和HIV治疗、信号通路的调节和肿瘤激活蛋白的抑制方面的生物应用详细介绍订书肽的最新进展。

Regulation of a variety of biological processes depends on the protein-protein interactions. Generally, the protein-protein interaction surface is too large to be selectively targeted by small molecule drugs. Besides, protein drug candidates cannot be used directly for this purpose because of their low cellular membrane permeability. Due to these problems,it is imperative to develop the next-generation therapeutic arsenals that combine the membrane permeability of small organic molecules w ith the broad targetability of protein-based drugs. To overcome this challenge,Verdine et al. designed a novel kind of peptides that w ere designated as hydrocarbon-stapled α-helical peptides. The synthetic mini-protein can strongly confine its conformation into α- helix by introducing an all-hydrocarbon chemical brace. The pharmacology of the stapled peptides,compared w ith their unstapled counterpart,is greatly improved,including enhancing proteolytic resistance and cellular permeability. In this paper,w e w ill review the recent advances of the stapled peptides in respect of their chemical synthesis,biophysical properties and pharmaceutical applications of them in the cancer-,and HIV- associated treatment,the regulation of signal pathw ay and the repression of tumor-activated proteins.