SELF-ASSEMBLY OF CYCLIC-PEPTIDES ON A DENDRIMER - MULTIPLE CYCLIC ANTIGEN PEPTIDES

Multiple cyclic antigen peptides (McAPs) are dendrimers that have bran ched, 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 i n solution after their cleavage from the resin with all protecting gro ups removed. The conceptual framework of our approach is the developme nt of a method favoring intrachain cyclization based on ring-chain tau tomerism between an N-terminal Cys and an aldehyde attached to the sid e 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 tri alkylphosphine is used to deblock Cys(St-Bu) on the amino terminus and to effect the concomitant thiazolidine formation with the glyoxyl moi ety obtained from an oxidative conversion of the Ser on the Lys side c hain. Two McAPs, each containing cyclic peptides of 17 and 24 amino ac id residues, have been prepared. To evaluate intrachain cyclization yi elds, a cleavage site as Asp-Pro is incorporated at the COOH terminus of each monomeric loop and subsequently released after completion of t he cyclization by treatment with formic acid at an elevated temperatur e. Reversed-phase high-performance liquid chromatography analyses of t he liberated cyclic peptide monomer with synthetic standards support t he theory that intrachain cyclization is the predominant cyclization p athway and validate the usefulness of this ring-chain tautomerization concept in the self-assembly of cyclic peptides on a branched peptide dendrimer.