Effect of N-alpha-acyl chain length on the membrane-modifying properties of synthetic analogs of the lipopeptaibol trichogin GA IV

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-alpha-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.