Death and the cancer cell. Macromolecular peptidomimetic manipulation of apoptosis. Cells of higher eukaryotes contain extrinsic receptor pathways and intrinsic pathways that activate effector caspases and induce apoptosis. (Right) The extrinsic cell death pathway is mediated by a subgroup of the TNF receptor superfamily called the death receptors (TNFR1, FAS, and TRAIL). Receptor-mediated cell death is initiated by the recruitment of adaptor proteins, like FADD, which then bind to DED-containing procaspases to generate a death-inducing signaling complex (DISC) that leads to activation of caspase-8. Caspase-8 directly cleaves and activates caspase-3, the executioner enzyme of apoptosis. (Left) In the mitochondrial or intrinsic pathway, proapoptotic BCL2 family members BAX and BAK translocate to the mitochondria. The BH3-only protein BID activates BAX and BAK to mediate the release of cytochrome c in the cytosol. This triggers the assembly of the apoptosome (APAF1 and caspase-9) and subsequent activation of caspase-3 and cell death. The SAHB BH3 peptidomimetic designed by Walensky et al. (3) mimics the BH3 helix of BID and hence is able to activate BAX and BAK, resulting in cytochrome c release from mitochondria. Inhibitor of apoptosis (IAP) proteins bind directly to caspases and inhibit their enzymatic activity. The inhibitory function of IAPs is countered by the second mitochondria-derived activator of caspases (SMAC). Four amino acid residues in the amino terminus of SMAC interact with the Bir domain of IAPs. Compound 3 designed by Li et al. (4) mimics the four amino-terminal residues of SMAC that interact with IAPs. This new molecule acts synergistically with TRAIL or TNF- to induce apoptosis of glioblastoma cells.
大多数的癌细胞由于凋亡机制不健全,所以导致恶性生长或者产生对抗肿瘤药物的抗性。由于蛋白间的互相作用在对细胞凋亡过程中起了决定性的调控作用,因此,利用具有生物活性的多肽来模拟蛋白互作,从而调控凋亡途径杀灭癌细胞的治疗策略,看起来是极具吸引力的。
然而,天然的多肽往往有生物利用率低、细胞膜穿透性弱和代谢稳定性差等局限,因此,一门新的学科应运而生——peptidomimetics,是指利用人工合成的物质模拟天然多肽的结构,或者利用构象性模板(conformational template)诱导相邻的多肽序列形成特异的结构。人工合成的或者改造过的多肽,力图保留天然的多肽的生物活性但克服其缺陷,以达到治疗所需要的要求。
在最新一期的《Science》(3 Sep, 2004)上,美国的两个研究组分别从细胞凋亡的固有途径和外来途径入手,利用这个peptidomimetics的策略启动细胞凋亡来治疗癌症。
在线粒体介导的凋亡途径(也就是固有途径)中,Bcl-2家族的各种蛋白起到了重要的调控作用。而这些蛋白都共有的结构域是BH3(BCL-2 homology 3) ,正是通过这个共同结构域,促进凋亡和抑制的蛋白互相作用,控制线粒体膜的整合性,一旦促进凋亡的蛋白形成优势,导致线粒体透性增加,释放细胞色素C等因子,启动整个细胞的凋亡。研究者合成改造后的BH3多肽"stabilized alpha-helix of BCL-2 domains" (SAHBs),SAHBs能够杀灭血癌细胞,并能阻止移植的血癌细胞在小鼠体能的生长。
另一篇文章,tumor necrosis factor (TNF ) 和 TNF-related apoptosis-inducing ligand (TRAIL),能够利用凋亡的外来途径活化caspases,最终杀灭癌细胞,但是细胞中存在的inhibitor-of-apoptosis protein (IAP)却抑制caspase的活性,不过,各种IAPs又可以被Smac所抑制。因此,研究者通过研究Smac和IAPs的结合部位的结构特性,合成了Smac的模拟物,并证明这种合成物能够和TNF 或TRAIL共同作用,杀灭癌细胞。
这两篇文章,分别出自细胞凋亡的大牛Korsmeyer和王晓东(都是和其他的实验室合作),而且,所用的方法,Korsmeyer还是偏向于动物模型和而王晓东则采用擅长的生化方法。不管怎样,二者都给出了peptidomimetics这个概念令人兴奋的证据。
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