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.
大多數(shù)的癌細胞由于凋亡機制不健全,，所以導致惡性生長或者產生對抗腫瘤藥物的抗性,。由于蛋白間的互相作用在對細胞凋亡過程中起了決定性的調控作用,，因此，利用具有生物活性的多肽來模擬蛋白互作，從而調控凋亡途徑殺滅癌細胞的治療策略，看起來是極具吸引力的。
然而,，天然的多肽往往有生物利用率低、細胞膜穿透性弱和代謝穩(wěn)定性差等局限,，因此,，一門新的學科應運而生——peptidomimetics，是指利用人工合成的物質模擬天然多肽的結構,，或者利用構象性模板（conformational template）誘導相鄰的多肽序列形成特異的結構,。人工合成的或者改造過的多肽，力圖保留天然的多肽的生物活性但克服其缺陷,，以達到治療所需要的要求,。
在最新一期的《Science》（3 Sep, 2004）上，美國的兩個研究組分別從細胞凋亡的固有途徑和外來途徑入手,，利用這個peptidomimetics的策略啟動細胞凋亡來治療癌癥,。
在線粒體介導的凋亡途徑（也就是固有途徑）中，Bcl-2家族的各種蛋白起到了重要的調控作用,。而這些蛋白都共有的結構域是BH3(BCL-2 homology 3) ,，正是通過這個共同結構域，促進凋亡和抑制的蛋白互相作用,，控制線粒體膜的整合性,，一旦促進凋亡的蛋白形成優(yōu)勢，導致線粒體透性增加,，釋放細胞色素C等因子,，啟動整個細胞的凋亡。研究者合成改造后的BH3多肽"stabilized alpha-helix of BCL-2 domains" (SAHBs),，SAHBs能夠殺滅血癌細胞,，并能阻止移植的血癌細胞在小鼠體能的生長。
另一篇文章,，tumor necrosis factor (TNF ) 和 TNF-related apoptosis-inducing ligand (TRAIL),，能夠利用凋亡的外來途徑活化caspases，最終殺滅癌細胞，但是細胞中存在的inhibitor-of-apoptosis protein （IAP）卻抑制caspase的活性,，不過,，各種IAPs又可以被Smac所抑制。因此,，研究者通過研究Smac和IAPs的結合部位的結構特性,，合成了Smac的模擬物，并證明這種合成物能夠和TNF 或TRAIL共同作用,，殺滅癌細胞。
這兩篇文章,，分別出自細胞凋亡的大牛Korsmeyer和王曉東（都是和其他的實驗室合作）,，而且，所用的方法,，Korsmeyer還是偏向于動物模型和而王曉東則采用擅長的生化方法,。不管怎樣，二者都給出了peptidomimetics這個概念令人興奮的證據(jù),。
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