Toward the rational design of cell fate modifiers: notch signaling as a target for novel biopharmaceuticals.
Toward the rational design of cell fate modifiers: notch signaling as a target for novel biopharmaceuticals.
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DOI：
10.2174/1389201003379013
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发表时间：
2000-06
影响因子：
2.8
通讯作者：
A. Zlobin;Jang Ms;L. Miele
中科院分区：
文献类型：
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作者：
A. Zlobin;Jang Ms;L. Miele
我们对控制细胞命运决定的高度保守机制的理解的最新进展，为合理设计调节特定细胞命运决定的生物制剂铺平了道路。导致增殖、分化或凋亡的细胞命运决定是无数人类疾病发病机制的关键因素。旨在调节体内或离体特定细胞类型的此类过程的生物制药在肿瘤学、干细胞技术、免疫调节和神经病理学方面具有巨大的潜在应用。控制细胞命运决定的最保守的机制之一是基于Notch-配体相互作用和随后的信号传导事件。最近的研究表明，这种机制在多种细胞成熟过程和肿瘤细胞中调节细胞分化、增殖和凋亡。这些观察结果表明，Notch 信号网络是多种适应症的有希望的药物靶点。在这篇综述中，我们描述了：1）Notch 信号网络中的潜在药物靶点； 2）目前已开发的Notch激动剂和拮抗剂，包括重组蛋白、抗体药物、合成肽、反义寡核苷酸和基因治疗方法，以及设计新型Notch靶向生物药物的可能策略； 3）此类生物药物的可能临床应用；4）选择和开发Notch靶向生物药物的模型策略。
Recent advances in our understanding of highly conserved mechanisms that control cell fate determination are paving the way towards rationally designed biologics that modulate specific cell fate decisions. Cell fate decisions leading to proliferation, differentiation or apoptosis are crucial elements in the pathogenesis of countless human diseases. Biopharmaceuticals designed to regulate such processes in specific cell types in vivo or ex vivo have vast potential applications in oncology, stem cell technology, immunomodulation and neuropathology. One of the most conserved mechanisms controlling cell fate determination is based upon Notch-ligand interactions and subsequent signaling events. Recent studies have shown that this mechanism regulates cell differentiation, proliferation and apoptosis in a wide variety of cell maturation processes and in neoplastic cells. These observations identify the Notch signaling network as a promising drug target for numerous indications. In this review, we describe: 1) potential drug targets in the Notch signaling network; 2) the Notch agonists and antagonists developed so far, including recombinant proteins, antibody-based agents, synthetic peptides, antisense oligonucleotides and gene therapy approaches, as well as possible strategies to design novel Notch-targeting biopharmaceuticals; 3) the possible clinical applications of such biopharmaceuticals and 4) a model strategy for the selection and developement of a Notch-targeting biopharmaceutical.