Peptide dendrimers as artificial enzymes, receptors, and drug-delivery agents

The dendritic architecture applied to peptides provides a practical entry into globular macromolecules resembling proteins. A modular design was chosen using a divergent synthesis on solid support alternating proteinogenic alpha-amino acids with branching diamino acids, producing peptide dendrimers with a molecular weight of 3-5 kDa. Initial studies focused on models for hydrolases and produced esterase peptide dendrimers featuring histidine as the key catalytic residue. Variations of amino acid composition and the branching diamino acid led to enantioselective catalysts. Rate accelerations of k(cat)/k(uncat) = 90 000 were obtained when the design was changed to monomeric peptide dendrimers alternating two amino acids with the branching unit. A combinatorial approach was developed allowing for the preparation of large libraries (> 60 000 members), which were screened for B-12 binding and catalytic activity. The peptide dendrimers were also investigated for drug delivery. Glycopeptide dendrimers conjugated to colchicine selectively inhibited the proliferation of targeted cells, whereas colchicine alone displayed high toxicity.