Zebrafish Model for Identifying P-glycoprotein Inhibitors

描述（由申请方提供）：外排转运蛋白因其在药物摄取、分布和排泄中的重要性而对药物开发特别感兴趣。研究最多的外排转运蛋白是P-糖蛋白（P-gp），它是由多药耐药基因（MDR）编码的ATP依赖性药物转运蛋白家族。P-gp已被证明是最重要的外排转运蛋白，因为它参与介导>50%的常用处方药物的转运，并对药物吸收、分布、代谢和排泄具有显著影响。P-gp作为血脑屏障（BBB）的守门人，其主动介导药物从脑到血液的小分子流出，并且其抑制导致药物在中枢神经系统（CNS）中滞留。设计不是P-gp底物的药物是增加CNS中药物渗透性的一种策略。或者，治疗性化合物可以与P-gp抑制剂共处理以增加药物渗透性。该SBIR旨在开发一种体内斑马鱼生物测定法来鉴定潜在的P-gp抑制剂。斑马鱼作为模式生物，具有离体发育、胚胎透明、成本低等优点。这种新的动物模型将有助于简化CNS疾病的药物发现和开发工作。对于主要的脑部疾病，包括阿尔茨海默氏病、帕金森氏病、亨廷顿病、ALS（肌萎缩性侧索硬化症）、多发性硬化症、脑癌、中风、脑损伤、自闭症、溶酶体贮积症、遗传性共济失调和失明，大多数治疗剂对BBB是不可渗透的，并且必须通过直接注射到脑或脑脊液中侵入性地递送，或者从可植入装置释放。给予P-gp抑制剂可增强药物递送和功效。这种斑马鱼生物测定将有助于简化CNS疾病的药物发现和开发工作。

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.