103(P-60) アンフォテリシンB連結分子の構造とイオンチャネル活性(ポスター発表の部)

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Polyenemacrolides such as amphotericin B (AmB) were thought to assemble together and form an ion channel across plasma membranes. Their antimicrobial activity has been accounted for by this assemblage, whose stability and activity are dependent on sterol constituents of lipid bilayer membrane. We attempted to solve the structure of this channel-like assemblage. For this purpose, several cross-linked molecules such as AmB dimers, AmB-phospholipid and AmB-sterol were synthesized and tested for their channel-forming activity. Among these, AmB dimers 3 and 4 that bore an aminoalkyl-dicarboxylate tether linked between amino groups of AmB showed potent hemolytic activity. Furthermore, pH measurements of liposome lumen by ^<31>P NMR, which led to evaluate K^+ entry, revealed that dimers 3 and 4 formed the similar molecular assemblage to that of AmB in phospholipid membrane. Judging from changes in ^<31>P NMR spectra, the dimers induced "all-or-none"-type ion flux across liposome membrane in the presence of ergosterol, hence indicating that ion-channel formed by ergosterol/dimer 3 or 4 mimicked that of AmB. To evaluate the interaction between AmB and membrane lipids in the ion channel complex, the conjugates of AmB-phospholipid, AmB-cholesterol, and AmB-ergosterol were prepared and tested for hemolytic assays and the ^<31>P NMR channel assays, where minor but important modification had been done; AmB was initially added before preparation of liposomes in lieu of adding to liposome suspensions. In this assay, AmB revealed the prominent ion permeability without sterol. This fact implies that sterol, particularly cholesterol, is not necessary for formation of ion channels, though possibly playing an essential role in the process of binding or penetrating of AmB to phospholipid membranes. Phospholipid conjugates (5), which revealed moderate hemolytic activity, appeared to form the stable assemblage, which showed less dependence on sterol constituent of lipid membrane. With these data in hand, we are now trying to elucidate the structure of the ion-channel complex by making the labeled conjugates of AmB for solid state NMR measurements.
天然有機化合物討論会の論文
2001-09-01

103(P-60) アンフォテリシンB連結分子の構造とイオンチャネル活性(ポスター発表の部)

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