title: Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane.
abstract: 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, 7α-OH-AmB, and 7β-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.
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan; JST, ERATO, Lipid Active Structure Project, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: JST, ERATO, Lipid Active Structure Project, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan; Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Umegawa
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuchikawa
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Matsumori
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Hanashima
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan; JST, ERATO, Lipid Active Structure Project, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan. Electronic address: murata@chem.sci.osaka-u.ac.jp.
authors.forename: Michio
authors.initials: M
authors.lastname: Murata
authors.affiliation: Department of Chemistry, University of Leicester, Leicester LE1 7RH, England, United Kingdom.
authors.forename: Resul
authors.initials: R
authors.lastname: Haser
authors.affiliation: Department of Chemistry, University of Leicester, Leicester LE1 7RH, England, United Kingdom.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Rawlings
authors.affiliation: School of Biomolecular and Biomedical Science, Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Caffrey
mesh_terms: D000666:Amphotericin B / Q000378:metabolism*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008051:Lipid Bilayers; D008081:Liposomes; D018942:Macrolides; D008958:Models, Molecular; D011108:Polymers / Q000378:metabolism*; D013261:Sterols / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D008051:Lipid Bilayers; D008081:Liposomes; D018942:Macrolides; D011108:Polymers; D013261:Sterols; C024617:polyol; D000666:Amphotericin B
keywords: Amphotericin B; Bioengineered analog; Liposomes; Macrolide; Sterol selectivity