Synthesis of a 19-residue peptide with alamethicin-like activity

Abstract

This paper describes the chemical synthesis of a compound with voltage-gating characteristics similar to those observed in nerve membranes. For alamethicin (ALA), a natural antibiotic that induces such properties in lipid bilayer membranes, there are two proposed structures, one a cyclic and the other an open chain peptide. The open chain sequence (ALA-o) proposed by Martin and Williams [(1976) Biochem. J. 153, 181-190] was synthesized by stepwise solid-phase condensation of four fragments prepared by solid-phase synthesis. The product, purified to homogeneity, was not identical with the main component of natural ALA. Nevertheless, in lipid bilayer membranes the exponential dependence of conductance on voltage and the dependence of conductance on a high power of the peptide concentration were qualitatively similar for ALA-o and for natural ALA. Like ALA, ALA-o showed the characteristics of a channel-former, although the single-channel conductances were less well defined for the synthetic compound. This work establishes that a cyclic structure is not a necessary condition for a peptide to induce voltage-dependent conductances in membranes and that ALA-o possesses all the structural elements required for such an activity.