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

Abstract

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-OMe11] analogs carrying at the N-terminus an acyl chain of variable length (C2−C8, C10, C12, C14, C16, C18). 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 Nα-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.

Conformation and membrane activity of an analogue of the peptaibol antibiotic trichogin GA IV with a lipophilic amino acid at the N-terminus

“…with trichogin GA IV itself may well be associated with the higher number of carbon atoms present in the lipophilic chain of the former peptide. In fact, we have already shown [3] that the membrane activity of trichogin GA IV increases with increasing number of carbon atoms in the N h -blocking fatty acyl moiety.…”

“…In these lipopeptides, a N h -blocking fatty acyl moiety of at least six carbon atoms is required for the onset of significant membrane activity [3]. In an NMR investigation in an aqueous solution containing SDS micelles we have shown that the acyl chain interacts intramolecularly with the first four amino acid residues [4].…”

Orientation and immersion depth of a helical lipopeptaibol in membranes using TOAC as an ESR probe

“…The synthesis and characterization of Z-Gly-Leu-Aib-Gly 2 -Leu-Aib-Gly-Ile-Leu-OMe (Z: benzyloxycarbonyl) and its short sequences have already been reported. 26 As TOAC is unstable under the acidic and reducing conditions required to remove the classical tert-butyloxycarbonyl and Z groups, respectively, the Fmoc N ␣ -protecting group was chosen SCHEME 1…”

“…The spectrum of [Leu-OMe 11 ] trichogin GA IV 26 is also reported for comparison. In this alcohol all of the spectra exhibit a negative maximum at 206 -204 nm ( 3 * peptide transition) and a less intense negative shoulder at 229 -222 nm (n 3 * peptide transition).…”

“…26 Several [CH 3 (CH 2 ) n CO-Aib 0 , Leu-OMe 11 ] trichogin analogues bearing at the N-terminus an acyl chain of different length have been synthesized. We have demonstrated that a trichogin analogue should contain at least six carbon atoms in the N-terminal acyl moiety in order to display significant membrane activity.…”