Peptide dendrimers are branched polypeptides and represent a cost-effective approach to design bioactive peptides by amplifying peptides of various lengths. They have the advantages in the ease of synthesis and in the increase of binding affinity to protein targets by virtue of their multivalency. Here we report on the development of peptide dendrimers as as anti-infectives and anti-proliferatives.
For anti-proliferatives, we have designed tunable peptide dendrimers that are membrane-permeable and are capable to inhibit intracellular protein-protein interaction. We were able to develop such a design by combining both intracellular delivery and functional roles in a single moiety with high efficiency and specificity. An advantage of the dendrimer peptide is that it avoids the conventional design of a bipartite construct consisting of a functional cargo and a cell penetrating peptide (CPP) as transportant. An example of our design is D4R which contains four tetrapeptide (RLYR) strands linked to a branched trilysine scaffold. Modification of D4R at its N- or C-terminus with small-molecular chemicals showed extraordinary specificity of delivery to subcellular compartments. Epi-fluorescence microscopy showed that they can penetrate into the most densely-packed cellular compartments such as the nucleolus and the mid-body during mitosis in HeLa or MCF-7 cells. Cold treatment and ATPase inhibitor showed that their translocation is direct and independent of both endocytosis and ATP-dependent process. When coupled to a 19-residue p21 antitumor peptide, D4R also served effectively as a transportant in cargo delivery to enhance apoptosis. Combining peptide dendrimers with small chemical moieties could lead to an approach to develop useful organelle-specfic cell-permeable intracellular inhibitors for laboratory and therapeutic uses.