470954 Pepdarts: Novel Peptide Vectors for Drug Delivery to the Brain

Thursday, November 17, 2016: 3:51 PM
Continental 7 (Hilton San Francisco Union Square)
Akanksha Sharma1, Jun Ha Kwak1, Divya Shastry2, John Trasatti3 and Pankaj Karande4, (1)Howard P. Isermann Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY, (2)Biochemistry & Biophysics, Rensselaer Polytechnic Institute, Troy, NY, (3)Chemistry, Rensselaer Polytechnic Institute, Troy, NY, (4)Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY

Delivery of biological cargo across the blood brain barrier (BBB) for therapeutic interventions is critical in treating neurological and neurodegenerative diseases but remains a formidable challenge. The BBB poses a strong physical and metabolic barrier for exchange of xenobiotics between systemic circulation and the central nervous system. Strategies employing the transcellular transport pathway of circulatory proteins such as transferrin have shown some success in this respect. We aim to employ the complementary paracellular pathway between the endothelial cells of the brain capillary microvasculature for transporting therapeutics to the central nervous system. Conventionally regarded as being reserved exclusively for the transport of small molecules and ions, there is some evidence that pathogens and immunomodulatory agents such as cytokines and immune cells can indeed access this pathway by disrupting the tight junctions (TJs) between the brain endothelial cells. TJs are non-covalent protein assemblies formed by extracellular loops (ECLs) of transmembrane proteins on endothelial cell surfaces. Claudin 5 (cldn5) has been identified as the key component of BBB TJs. Animal models representing cldn5-knockouts exhibit an easily accessible central nervous compartment to molecules in systemic circulation but fail to survive beyond the neonatal stage.

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.

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See more of this Session: Protein Engineering III: Therapeutics
See more of this Group/Topical: Food, Pharmaceutical & Bioengineering Division