TY - JOUR
T1 - An amphotericin B-ergosterol covalent conjugate with powerful membrane permeabilizing activity
AU - Matsumori, Nobuaki
AU - Eiraku, Noritsugu
AU - Matsuoka, Shigeru
AU - Oishi, Tohru
AU - Murata, Michio
AU - Aoki, Takaaki
AU - Ide, Toru
N1 - Funding Information:
We are grateful to Prof. Yuzuru Mikami, Research Center for Pathogenic Fungi and Microbial Toxicoses, Chiba University, for antifungal assays. This work was supported by a Grant-In-Aid for Scientific Research on Priority Area (A) (No. 12045235) from the Ministry of Education, Culture, Sports, Sciences, and Technology, Japan; by a grant from the CREST, Japan Science and Technology Corporation; and by the Yamada Science Foundation.
PY - 2004/5
Y1 - 2004/5
N2 - Amphotericin B-sterol conjugates were synthesized and examined for their membrane permeabilizing activity. Ergosterol and cholesterol, each connected with amphotericin B via an ethylenecarbamate or hexamethylenecarbamate linker, were examined by K+ flux assays using liposomes and by single-channel recording across phospholipid membrane. Among four conjugates tested, AmB-ergosterol bearing an ethylenecarbamate linker exhibited the most powerful activity, which substantially exceeded that of the cholesterol homolog. Single-channel recording clearly exhibited that the ergosterol conjugate elicited channel current with the conductance of 28 pS, which was comparable with those by AmB, and revealed a higher channel open probability than the cholesterol conjugate. These results imply that direct interaction between amphotericin B and ergosterol is reproduced by their conjugate, which may serve as a model compound for understanding the drug's selective toxicity.
AB - Amphotericin B-sterol conjugates were synthesized and examined for their membrane permeabilizing activity. Ergosterol and cholesterol, each connected with amphotericin B via an ethylenecarbamate or hexamethylenecarbamate linker, were examined by K+ flux assays using liposomes and by single-channel recording across phospholipid membrane. Among four conjugates tested, AmB-ergosterol bearing an ethylenecarbamate linker exhibited the most powerful activity, which substantially exceeded that of the cholesterol homolog. Single-channel recording clearly exhibited that the ergosterol conjugate elicited channel current with the conductance of 28 pS, which was comparable with those by AmB, and revealed a higher channel open probability than the cholesterol conjugate. These results imply that direct interaction between amphotericin B and ergosterol is reproduced by their conjugate, which may serve as a model compound for understanding the drug's selective toxicity.
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U2 - 10.1016/j.chembiol.2004.02.027
DO - 10.1016/j.chembiol.2004.02.027
M3 - Article
C2 - 15157878
AN - SCOPUS:2642544178
SN - 2451-9448
VL - 11
SP - 673
EP - 679
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 5
ER -