Glycopeptides related to β-endorphin adopt helical amphipathic conformations in the presence of lipid bilayers

被引：34

作者：

Dhanasekaran, M ^{[1
]}

Palian, MM ^{[1
]}

Alves, I ^{[1
]}

Yeomans, L ^{[1
]}

Keyari, CM ^{[1
]}

Davis, P ^{[1
]}

Bilsky, EJ ^{[1
]}

Egleton, RD ^{[1
]}

Yamamura, HI ^{[1
]}

Jacobsen, NE ^{[1
]}

Tollin, G ^{[1
]}

Hruby, VJ ^{[1
]}

Porreca, F ^{[1
]}

Polt, R ^{[1
]}

机构：

[1] Univ Arizona, Dept Chem, Carl S Marvel Labs, Tucson, AZ 85721 USA

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2005年 / 127卷 / 15期

关键词：

D O I：

10.1021/ja0432158

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

A series of glycosylated endorphin analogues designed to penetrate the blood-brain barrier (EBB) have been studied by circular dichroism and by 2D-NMR in the presence of water; TFE/water; SDS micelles; and in the presence of both neutral and anionic bicelles. In water, the glycopeptides showed only nascent helix behavior and random coil conformations. Chemical shift indices and nuclear Overhauser effects (NOE) confirmed helices in the presence of membrane mimics. NOE volumes provided distance constraints for molecular dynamics calculations used to provide detailed backbone conformations. In all cases, the glycopeptides were largely helical in the presence of membrane bilayer models (micelles or bicelles). Plasmon waveguide resonance (PWR) studies showed hen egg phosphatidyl choline (PC) bilayers produce amphipathic helices laying parallel to the membrane surface, with dissociation constants (K-D) in the low nanomolar to micromolar concentration range. Two low-energy states are suggested for the glycosylated endorphin analogues, a flexible aqueous state and a restricted membrane bound state. Strong interactions between the glycopeptide amphipaths and membranes are crucial for penetration of the BBB via an endocytotic mechanism (transcytosis).

引用

页码：5435 / 5448

页数：14

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