Total synthesis and further characterization of the .gamma.-carboxyglutamate-containing "sleeper" peptide from Conus geographus venom

Publisher Website
Google Scholar
Abstract
The total synthesis of the Gla-containing"sleeper" peptide (Gly-Glu-Gla-Gla-Leu-Gln-Gla-Asn-Gln-Gla-Leu-Arg-Gla-Lys-Ser-Asn-NH2) from Conus geographus is described. A new strategy for the synthesis of acid-sensitive peptide amides was developed, which allowed complete deprotection and cleavage of the LK-.gamma.-carboxyglutamate-containing peptide from the 2,4-dimethoxybenzhydrylamine resin. Synthetic sleeper peptide, after preparative high-performance liquid chromatography (HPL-C) purification, was shown to be identical with the native peptide by all criteria (coelution experiments on HPLC, sequence analysis, and biological activity). In addition, a developmental switch in the behavioral symptoms induced by the peptide after intracerebral administration in mice was documented. At low doses of the peptide (4-30 pmol/g), a sleeplike state was induced in mice under 2 weeks old; in contrast, older mice became markedly hyperactive. It is proposed that, in the presence of Ca2+, the sleeper peptide assumes an .alpha.=helical configuration in which all the .gamma.-carboxyglutamate residues are located on the same side of the .alpha.-helix.