Exploration of backbone space in foldamers containing α- and β-amino acid residues:: Developing protease-resistant oligomers that bind tightly to the BH3-recognition cleft of Bcl-xL
Exploration of backbone space in foldamers containing α- and β-amino acid residues:: Developing protease-resistant oligomers that bind tightly to the BH3-recognition cleft of Bcl-xL
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DOI：
10.1002/cbic.200600546
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发表时间：
2007-05-25
期刊：
影响因子：
3.2
通讯作者：
Gellman, Samuel H.
中科院分区：
文献类型：
--
作者：
Sadowsky, Jack D.;Murray, Justin K.;Gellman, Samuel H.
蛋白质-蛋白质相互作用在细胞信号事件中起着至关重要的作用，并且通常与人类疾病有关。与功能性蛋白质表面位点紧密结合并对降解酶表现出hgih稳定性的分子可能是解剖细胞信号网络的有价值的药理学工具，并可能最终产生治疗剂。我们最近描述了含有α-和β-氨基酸残基的寡聚体，其与抗凋亡蛋白Bcl-x（L）的BH 3识别位点紧密结合。具有最高亲和力的寡聚体具有9个残基的N-末端区段和6个残基的C-末端区段，所述9个残基的N-末端区段具有1：1的α：β残基重复，所述6个残基的C-末端区段仅含有蛋白原α-残基。这种（α/β + α）-肽的N-末端部分对蛋白水解具有高度抗性，但C-末端α-区段是敏感的。这项研究来自于以减少蛋白水解降解但保留对Bcl-x（L）的高亲和力的方式修饰（α/β + α）肽中的α片段的努力。这里报道的一些低聚物可以证明在某些生物应用中是有用的，特别是那些需要在生物环境中延长孵育的应用。
Protein-protein interactions play crucial roles in cell-signaling events and are often implicated in human disease. Molecules that bind tightly to functional protein-surface sites and show hgih stability to degradative enzymes could be valuable pharmacological tools for dissection of cell-signaling networks and might ultimately lead to thereapeutic agents. We recently described oligomers containing both alpha- and beta-amino acid residues that bind tightly to the BH3 recognition site of the anti-apoptotic protein Bcl-x(L). The oligomers with the highest affinity had a nine-residue N-terminal segment with a 1:1 alpha:beta residue repeat and a six-residue C-terminal segment containing exclusively proteinogenic alpha-residues. The N-terminal portions of such (alpha/beta + alpha)-peptides are highly resistant to proteolysis, but the C-terminal alpha-segments are susceptible. This study emerged from efforts to modify the alpha-segment in an (alpha/beta + alpha)-peptide in a way that would diminish proteolytic degradation but retain high affinity for Bcl-x(L). Some of the oligomers reported here could prove useful in certain biological applications, particularly those for which extended incubation in a biological milieu is required.