Derivatization and Isotope Labeling of Amphotericin B Aiming at Elucidation of the Ion-channel Structure

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  • Matsumori Nobuaki
    Department of Chemistry, Graduate School of Science, Osaka University
  • Oishi Tohru
    Department of Chemistry, Graduate School of Science, Osaka University
  • Murata Michio
    Department of Chemistry, Graduate School of Science, Osaka University

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  • 誘導体および同位体標識化合物を用いたアンフォテリシンＢイオンチャネル構造の解明
  • ユウドウタイ オヨビ ドウイタイ ヒョウシキ カゴウブツ オ モチイタ アンフォテリシン Bイオンチャネル コウゾウ ノ カイメイ

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Abstract

Amphotericin B (AmB) is known to assemble together and form an ion channel across biomembranes. The selective toxicity is generally accounted for by its higher affinity for ergosterol than cholesterol. To better understand the ion-channel structure and intermolecular interactions, we prepared various AmB derivatives and measured their activities. AmB dimers which are covalently linked between the amino groups by short chains showed more potent ion-channel activity than that of AmB, indicating that the mutual topology of AmB molecules is a head-to-head orientation. AmB-sterol conjugates were also designed and examined for ion-channel activities. AmB-ergosterol conjugates showed more powerful ion-channel activity than AmB-cholesterol congeners, suggesting that stronger van der Waals interaction between AmB and ergosterol contributes to the higher ion-channel activity. Finally, we prepared conformation-restricted derivatives of AmB, in which the amino and carboxyl groups were bridged with various lengths of alkyl chains. The derivatives successfully gave us information on the active-conformation of the sugar moiety of AmB in membrane. These derivatives are now labeled by 13C and/or 19F to probe the molecular structure of AmB ion channel using solid-state NMR.

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