Effect of N~α-Acyl Chain Length on the Membrane-Modifying Properties of Synthetic Analogs of the Lipopeptaibol Trichogin GA Ⅳ

摘要

Trichogin GA Ⅳ, an 11-residue lipopeptaibol blocked at the N-terminus by an n-octanoyl group and at the C-terminus by a 1,2-amino alcohol (L-leucinol), extracted from the fungus Trichoderma longibrachiatum, exhibits remarkable membrane-modifying properties. We have synthesized trichogin GA Ⅳ and several [L-Leu-OMe~(11)] analogs carrying at the N-terminus an acyl chain of variable length (C_2-C_8, C_(10), C_(12), C_(14), C_(16), C_(18)). A succinoylated head-to-head dimer was also prepared. A conformational analysis, carried out by FTIR absorption, CD, and NMR, showed that the right-handed helical structure of the natural lipopeptaibol is essentially preserved in all its analogs. Permeability measurements revealed that at least six carbon atoms in the N~α-blocking fatty acyl moiety are required for the onset of significant membrane-modifying properties. Also the head-to-head dimer is remarkably active. Possible models for the mechanism of membrane permeability of trichogin GA Ⅳ are discussed.