TY - JOUR
T1 - Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane
AU - Yamamoto, Tomoya
AU - Umegawa, Yuichi
AU - Tsuchikawa, Hiroshi
AU - Matsumori, Nobuaki
AU - Hanashima, Shinya
AU - Murata, Michio
AU - Haser, Resul
AU - Rawlings, Bernard J.
AU - Caffrey, Patrick
N1 - Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.
PY - 2015/4/15
Y1 - 2015/4/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84946497899&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84946497899&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2015.07.009
DO - 10.1016/j.bmc.2015.07.009
M3 - Article
C2 - 26209267
AN - SCOPUS:84946497899
VL - 23
SP - 5782
EP - 5788
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 17
ER -