Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability.
Bridged beta(3)-peptide inhibitors of p53-hDM2 complexation: correlation between affinity and cell permeability.
复制标题
DOI：
10.1021/ja910715u
复制
发表时间：
2010-03-10
影响因子：
15
通讯作者：
Schepartz A
中科院分区：
文献类型：
--
作者：
Bautista AD;Appelbaum JS;Craig CJ;Michel J;Schepartz A
β-肽具有肽模拟物中所需的几个特征;它们易于合成，在生理缓冲液中折叠成稳定的二级结构，并抵抗蛋白水解。它们还可以与多种蛋白质结合，以抑制它们与α-螺旋配体的相互作用。然而，β-肽通常不是细胞可渗透的，并且这一特征限制了它们作为研究工具和潜在治疗剂的效用。将Arg 8序列与β-肽结合改善了摄取，但增加了相当大的质量。我们报告说，在PPII、α-或β-肽螺旋内嵌入一个小的阳离子补丁可以提高吸收，而不会增加显着的质量。在另一种质量中性策略中，Verdine、Walensky和其他人报道了在α-螺旋的i和i+4位置之间插入烃桥也会增加细胞摄取。在这里，我们描述了一系列含有二醚和烃桥的β-肽，并根据细胞摄取和定位、对hDM 2的亲和力和14-螺旋结构对它们进行比较。我们的结果突出了阳离子补丁和疏水桥策略用于改善β-肽摄取的相对优点，并确定了摄取效率和hDM 2亲和力之间令人惊讶的相关性。
β-peptides possess several features that are desirable in peptidomimetics; they are easily synthesized, fold into stable secondary structures in physiologic buffers, and resist proteolysis. They can also bind to a diverse array of proteins to inhibit their interactions with α–helical ligands. β–peptides are not usually cell permeable, however, and this feature limits their utility as research tools and potential therapeutics. Appending an Arg8 sequence to a β–peptide improves uptake but adds considerable mass. We reported that embedding a small cationic patch within a PPII, α– or β–peptide helix improves uptake without the addition of significant mass. In another mass-neutral strategy, Verdine, Walensky, and others have reported that insertion of a hydrocarbon bridge between the i and i+4 positions of an α–helix also increases cell uptake. Here we describe a series of β–peptides containing diether and hydrocarbon bridges and compare them on the basis of cell uptake and localization, affinities for hDM2, and 14-helix structure. Our results highlight the relative merits of cationic patch and hydrophobic bridge strategies for improving β–peptide uptake and identify a surprising correlation between uptake efficiency and hDM2 affinity.
登录
查看更多内容
影响因子：
7.8
作者：
Henchey, Laura K.;Jochim, Andrea L.;Arora, Paramjit S.
通讯作者：
Arora, Paramjit S.
DOI：
10.1034/j.1399-3011.1999.00131.x
发表时间：
1999-09-01
期刊：
JOURNAL OF PEPTIDE RESEARCH
影响因子：
--
作者：
DeGrado, WF;Schneider, JP;Hamuro, Y
通讯作者：
Hamuro, Y
影响因子：
15
作者：
Hart, SA;Bahadoor, ABF;Schepartz, A
通讯作者：
Schepartz, A
影响因子：
15
作者：
Goodman, Jessica L.;Petersson, E. James;Schepartz, Alanna
通讯作者：
Schepartz, Alanna
影响因子：
15
作者：
Kritzer, JA;Luedtke, NW;Schepartz, A
通讯作者：
Schepartz, A