摘要
Eph受体酪氨酸激酶及其肝配蛋白配体构成了一个重要的细胞信号转导系统并控制了组织平衡和许多病理的发展过程。不同的Eph受体/配体几乎存在于所有类型的细胞中,其表达往往因损伤和疾病而失调。因此,14 Eph受体作为一类主要的潜在药物靶点,引起越来越多的关注。特别是,这些受体结合细胞外结合肝配蛋白囊,显示了很好的医疗应用前景。该囊包括一个宽浅的凹槽,由几个有弹性的环包围,因而使多肽具有高亲和力和选择性,特别适合作为药物靶点。因此,一些多肽结合具有微摩尔亲和力的Eph受体,现已被噬菌体展示技术等方法确定。这些多肽可抑制蛋白结合和作为一般Eph受体/肝配蛋白信号的拮抗剂,但其中一些多肽作为激动剂模仿诱导Eph受体激活蛋白。重要的是,一些多肽是从单Eph受体中精心挑选所得,大多数确定的多肽结构为线性,但最近的环状支架具有相当大的优势已得到认可,特别是鉴于对先导药物进行潜在优化。到目前为止,肽的改进已获取了低纳摩尔Eph受体的衍生物,具有亲和力高,抗血浆蛋白酶和体内半衰期长等特点。除了调节Eph受体/蛋白功能外,多肽类也可为肿瘤提供共轭成像和治疗剂或不同类型的纳米粒子或为其他病变组织呈现Eph受体靶点。
关键词: 血管生成,癌症,环肽,线性肽,神经修复,神经变性疾病,蛋白 - 蛋白相互作用
图形摘要
Current Drug Targets
Title:Targeting the Eph System with Peptides and Peptide Conjugates
Volume: 16 Issue: 10
Author(s): Stefan J. Riedl and Elena B. Pasquale
Affiliation:
关键词: 血管生成,癌症,环肽,线性肽,神经修复,神经变性疾病,蛋白 - 蛋白相互作用
摘要: Eph receptor tyrosine kinases and ephrin ligands constitute an important cell communication system that controls development, tissue homeostasis and many pathological processes. Various Eph receptors/ephrins are present in essentially all cell types and their expression is often dysregulated by injury and disease. Thus, the 14 Eph receptors are attracting increasing attention as a major class of potential drug targets. In particular, agents that bind to the extracellular ephrin-binding pocket of these receptors show promise for medical applications. This pocket comprises a broad and shallow groove surrounded by several flexible loops, which makes peptides particularly suitable to target it with high affinity and selectivity. Accordingly, a number of peptides that bind to Eph receptors with micromolar affinity have been identified using phage display and other approaches. These peptides are generally antagonists that inhibit ephrin binding and Eph receptor/ ephrin signaling, but some are agonists mimicking ephrin-induced Eph receptor activation. Importantly, some of the peptides are exquisitely selective for single Eph receptors. Most identified peptides are linear, but recently the considerable advantages of cyclic scaffolds have been recognized, particularly in light of potential optimization towards drug leads. To date, peptide improvements have yielded derivatives with low nanomolar Eph receptor binding affinity, high resistance to plasma proteases and/or long in vivo half-life, exemplifying the merits of peptides for Eph receptor targeting. Besides their modulation of Eph receptor/ephrin function, peptides can also serve to deliver conjugated imaging and therapeutic agents or various types of nanoparticles to tumors and other diseased tissues presenting target Eph receptors.
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Cite this article as:
Stefan J. Riedl and Elena B. Pasquale , Targeting the Eph System with Peptides and Peptide Conjugates, Current Drug Targets 2015; 16 (10) . https://dx.doi.org/10.2174/1389450116666150727115934
DOI https://dx.doi.org/10.2174/1389450116666150727115934 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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