Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane

被引：13

作者：

Yamamoto, Tomoya ^{[1
,2
]}

Umegawa, Yuichi ^{[1
,2
]}

Tsuchikawa, Hiroshi ^{[1
]}

Matsumori, Nobuaki ^{[1
]}

Hanashima, Shinya ^{[1
]}

Murata, Michio ^{[1
,2
]}

Haser, Resul ^{[3
]}

Rawlings, Bernard J. ^{[3
]}

Caffrey, Patrick ^{[4
]}

机构：

[1] Osaka Univ, Grad Sch Sci, Dept Chem, Toyonaka, Osaka 5600043, Japan

[2] Osaka Univ, Lipid Act Struct Project, ERATO, JST, Toyonaka, Osaka 5600043, Japan

[3] Univ Leicester, Dept Chem, Leicester LE1 7RH, Leics, England

[4] Univ Coll Dublin, Ctr Synth & Chem Biol, Sch Biomol & Biomed Sci, Dublin 2, Ireland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 17期

基金：

日本科学技术振兴机构;

关键词：

Amphotericin B; Bioengineered analog; Liposomes; Sterol selectivity; Macrolide; POLYENE MACROLIDES; ANTIFUNGAL; BIOSYNTHESIS; ORGANIZATION; NYSTATIN; POSITION; BINDING; CELLS; YEAST; NMR;

D O I：

10.1016/j.bmc.2015.07.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Amphotericin B (AmB) is a polyene macrolide antibiotic widely used to treat mycotic infections. In this paper, we focus on the role of the polyol moiety of AmB in sterol selectivity using 7-oxo-AmB, 7 alpha-OH-AmB, and 7 beta-OH-AmB. The 7-OH analogs were prepared from 7-oxo-AmB. Their K+ flux activity in liposomes showed that introduction of an additional ketone or hydroxy group on the polyol moiety reduces the original activity. Conformational analyses of these derivatives indicated that intramolecular hydrogen-bonding network possibly influenced the conformational rigidity of the macrolactone ring, and stabilized the active conformation in the membrane. Additionally, the flexible polyol leads to destabilization of the whole macrolactone ring conformation, resulting in a loss of sterol selectivity. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：5782 / 5788

页数：7

共 41 条

[1] Amphotericin forms an extramembranous and fungicidal sterol sponge [J].