Self-assembly of cyclic peptides on a dendrimer: multiple cyclic antigen peptides.

Abstract

Multiple cyclic antigen peptides (McAPs) are dendrimers that have branched, multiple closed-chain architectures. We describe an approach for their stepwise, solid-phase synthesis that permits a self-assembly of cyclization reactions of a McAP with four copies of cyclic peptides in solution after their cleavage from the resin with all protecting groups removed. The conceptual framework of our approach is the development of a method favoring intrachain cyclization based on ring-chain tautomerism between an N-terminal Cys and an aldehyde attached to the side chain of Lys to form a loop linked by a thiazolidine ring. The McAP precursor contains an amino Cys(St-Bu) and an internal Lys(Ser). A trialklyphosphine is used to deblock Cys(St-Bu) on the amino terminus and to effect the concomitant thiazolidine formation with the glyoxyl moiety obtained from an oxidative conversion of the Ser on the Lys side chain. Two McAPs, each containing cyclic peptides of 17 and 24 amino acid residues, have been prepared. To evaluate intrachain cyclization yields, a cleavage site as Asp-Pro incorporated at the COOH terminus of each monomeric loop and subsequently released after completion of the cyclization by treatment with formic acid at an elevated temperature. Reversed-phase high-performance liquid chromatography analyses of the liberated cyclic peptide monomer with synthetic standards support the theory that intrachain cyclization is the predominant cyclization pathway and validate the usefulness of this ring-chain tautomerization concept in the self-assembly of cyclic peptides on a branched peptide dendrimer.