(524e) Discovery of Tight Junction Disrupting Peptides for Drug Delivery to the Brain

Currently, patients suffering from brain related disorders such as Alzheimer's, Parkinson's, Huntington's, epilepsy, stroke, brain tumors and sclerosis show very poor clinical outcome. Advances in basic neurobiology, medicinal chemistry, and protein and enzyme engineering have led to the discovery of a large number of potential therapeutics for treatment of brain related disorders. However, most candidate therapeutics will never make it to the clinic because their physico-chemical properties prevent them from crossing the blood brain barrier (BBB). We plan on addressing this important challenge by designing peptides that can selectively and reversibly permeabilize the BBB to therapeutic molecules. Specifically, we have discovered peptides that bind to claudin 5 an important transmembrane protein involved in the formation of tight junctions of the BBB. Claudin 5 binding peptides disrupt tight junctions of the BBB that are responsible for regulating transport across the BBB. Peptides are inexpensive as compared to fusion-protein or antibody-based therapeutics and are expected to show low toxicity and immune rejection. Further, our proposed strategy does not require chemical modification of the active drug, and can be used for delivery of promising candidates that have been discovered previously or are used in clinical settings with limited efficacy. If successful, this proposal will also provide a new lease on drugs that have failed due to poor brain penetration.