470954 Pepdarts: Novel Peptide Vectors for Drug Delivery to the Brain
Here, we report on the design and development of PEPDARTs, a suite of novel peptide vectors, designed specifically to target and transiently disrupt the cldn5 TJ assemblies of the brain capillary endothelial cells. PEPDARTs (Permeability Enhancing Peptides for Disruption, Attenuation & Recovery of Tight junctions) disrupt cldn5 TJ assemblies by binding to cldn5 ECLs and interfering with the homophilic cis- and trans-interactions of ECLs on the neighboring endothelial cells to enhance permeability across the BBB. Furthermore, since PEPDARTs are relatively small (10-15 amino acids) their circulation half-life is short (~30-45 minutes) causing quick clearance from the TJ interface and systemic circulation. Any disruption of the BBB is therefore anticipated to be transient under in vivo conditions.
We will present our preliminary studies from peptide microarrays and in vitro cell culture models that have led to fundamental understanding of the interactions between cldn5 ECLs (responsible for the formation of TJs). Additionally, these studies have led to the design of several PEPDART candidates that increase the BBB permeability at levels relevant for therapeutic applications. We will conclude with in vivo results in animal models demonstrating the transient and reversible disruption of the BBB in the presence of PEPDARTs. We are currently investigating the potency and safety of PEPDARTs in their efficacy and utility as drug delivery vectors for CNS-relevant therapeutics for delivery to the brain. This work is expected to not only have a significant impact on the development of new therapeutic modalities for treatment of NDs, but also elucidate the fundamental mechanisms of molecular transport across the BBB.