UNPROTECTED PEPTIDES AS BUILDING BLOCKS FOR THE SYNTHESIS OF PEPTIDE DENDRIMERS WITH OXIME, HYDRAZONE, AND THIAZOLIDINE LINKAGES

摘要

A general approach for forming peptide dendrimers with oxime, hydrazone, and thiazolidine linkages was developed using unprotected peptides as building blocks and selective ligation between an aldehyde and a weak base. To illustrate the generality of this approach, a branched lysine core matrix with an aldehyde was used to ligate four copies of unprotected peptides containing a weak nucleophilic base such as aminooxy, hydrazide, or cysteine 1,2-aminothiol groups at their N-termini to form synthetic branched proteins. Various parameters affecting the ligations were studied, and optimal conditions gave 12-27-fold rate increases and shortened the reaction time from 24-60 to 2-8 h. Among the three reactions studied, ligation by thiazolidine appeared to be superior to ligation by oxime or hydrazone in reaction rate and product stability. The purified dendrimeric products gave single peaks on reverse phase HPLC and size exclusion HPLC. Their macromolecular structures were also characterized by mass spectrometry and amino acid analysis. Circular dichroism spectra of the dendrimers showed that they have an increased ordered helical structure. Ligation reactions using a mutually reactive weak base and aldehyde pair should provide a useful approach for the synthesis of peptide dendrimers and artificial proteins. [References: 45]