Zebrafish Model for Identifying P-glycoprotein Inhibitors

DESCRIPTION (provided by applicant): Efflux transporters are of particular interest for drug development because of their importance in drug uptake, distribution and excretion. The most widely studied efflux transporter is P-glycoprotein (P-gp), a family of ATP-dependent drug transport proteins, which is encoded by multidrug resistance genes (MDR). P-gp has been shown to be the most important efflux transporter since it is involved in mediating transport of >50% of commonly prescribed drugs and to have a significant effect on drug absorption, distribution, metabolism and excretion. P-gp serves as a blood brain barrier (BBB) gatekeeper which actively mediates drug efflux of small molecules from the brain to blood, and its inhibition leads to drug retention in the central nervous system (CNS). Design of drugs that are not P-gp substrates is one strategy to increase drug permeability in the CNS. Alternatively, therapeutic compounds can be co-treated with P-gp inhibitors to increase drug permeability. This SBIR aims to develop an in vivo zebrafish bioassay to identify potential P- gp inhibitors. As a model organism, zebrafish offers several advantages for compound screening, including ex uterus development, transparency of the embryo and low cost. This new animal model will help to streamline drug discovery and development efforts for CNS diseases. For major brain disorders, including Alzheimer's, Parkinson's, Huntington's disease, ALS (amyotrophic Lateral Sclerosis), multiple sclerosis, brain cancer, stroke, brain injury, autism, lysosomal storage disorders, inherited ataxias and blindness, most therapeutics are impermeable to the BBB and must be delivered invasively by direct injection into the brain or cerebrospinal fluid, or released from an implantable device. Administration of P-gp inhibitors may enhance drug delivery and efficacy. This zebrafish bioassay will help to streamline drug discovery and development efforts for CNS diseases.