(256f) Transferrin Mediated Drug Delivery to Brain

Drug delivery to the brain is a significant challenge due to the presence of the formidable blood-brain barrier (BBB). Current therapeutic interventions to treat brain disorders include surgical implants or catheters, both of which are highly invasive and carry the risk of long term neurological damage. In contrast, non-invasive strategies based on endogenous transport pathways in the brain, such as the receptor-mediated transcytosis (RMT) pathway, are attractive alternatives for brain drug delivery. We are developing a novel drug delivery strategy based on short peptides that bind to human transferrin (hTf), and can be used to deliver drugs via RMT of hTf. It is known that several bacterial species have evolved surface proteins that bind to hTf in serum. These proteins, called transferrin binding proteins (Tbp), enable the pathogens to scavenge iron from circulating hTf, and use it for their own metabolic requirements. hTf receptors on different pathogens therefore offer a potential search space for designing peptide chaperones that bind to hTf. These chaperones can potentially enable the delivery of a drug cargo across the BBB via the natural endogenous RMT of hTf. Various transferrin binding proteins of type B (TbpB) from M. catarrhalis were selected for the purpose of this study to demonstrate the feasibility of our approach. hTf-binding peptides from TbpB sequences of M. catarrhalis were identified by high-throughput screening of libraries on peptide microarrays. We have identified several short 15-mer peptides that bind to hTf with very high affinity (<10 nM). Since these peptides are obtained from a non-human protein, they are less likely to compete with the binding of hTf to human receptors, or interfere with the endogenous RMT of hTf into brain. The discovery of peptide chaperones that bind to hTf will have a significant impact on therapeutic interventions in central nervous system disorders.