Evaluation of a Brain Endothelium Transmembrane Protein as a Therapeutic Target for Drug Delivery across the Blood Brain Barrier

神经系统疾病，特别是癌症和脑部感染，是医疗保健面临的一个重大挑战 供应商和药物开发商一样。大多数治疗剂不能穿过血脑屏障（BBB）， 维持神经元功能的最佳环境。目前的治疗努力集中在开发 药物递送系统和靶向药物，允许治疗剂以安全有效的方式穿过BBB， 方式Vertex认识到替代和新兴药物模式的潜力，重要的是， 靶向药物输送的可能性。随着人们对神经系统疾病的兴趣日益浓厚，Vertex 旨在探索新的材料，提供穿透血脑屏障的分子，首先作为一种工具， 研究，并最终作为一个平台，为批准的治疗疾病。最近发现的跨膜 一种选择性地在脑内皮上表达的蛋白质，作为运输 对于Vertex来说，跨血脑屏障的药物分子是有吸引力的，因为它是一个潜在的靶点，可以特异性地将药物递送到 大脑鉴定一种能与这种跨膜蛋白特异性结合的肽可能会提供一个锚 用于开发靶向药物输送材料。噬菌体展示代表了一种方法， 被用来发现识别细胞表面受体的分子（在这种情况下是肽）。违反 传统的噬菌体展示只允许编码和选择基于肽的文库，Derda组 在阿尔伯塔大学，他开发了一种方法，用于化学翻译后修饰， 噬菌体展示文库以引入超过传统20个氨基酸的非天然部分。从这样的混合 可以快速鉴定以高特异性靶向脑特异性跨膜蛋白的配体 和亲和力。该项目将集中于识别选择性结合脑特异性的配体。 跨膜蛋白，具有这些配体的材料的功能化，以及这些配体的评估， 用于促进从微脉管系统到脑实质的增加的摄取的材料。

Neurological diseases, especially cancers and infections of the brain, present a major challenge to health care providers and drug developers alike. Most therapeutics cannot cross the blood brain barrier (BBB), which maintains the optimal environment for neuronal function. Current efforts in therapeutics focus on developing drug-delivery systems and targeted drugs that allow therapeutics to cross the BBB in a safe and effective manner. Vertex realizes the potential of alternate and emerging drug modalities and, importantly, the possibilities for targeted drug delivery. With the growing interest in neurological disorders in mind, Vertex aims to explore new materials that provide penetration of the BBB to its molecules, first as a tool for early research, and ultimately as a platform for approved treatments of disease. A recently identified transmembrane protein that is selectively expressed on the brain endothelium and acts as a regulator of the transport of molecules across the BBB is attractive to Vertex as a potential target for delivering medicines specifically to the brain. Identifying a peptide that binds specifically to this transmembrane protein might provide an anchor for the development of materials for targeted drug delivery. Phage display represents one approach that has been leveraged to discover molecules (peptides in this case) that recognize cell-surface receptors. Contrary to traditional phage display that allows for encoding and selection of peptide-based libraries only, the Derda group at the University of Alberta developed methodology for chemical post-translational modification of phage-displayed libraries to introduce unnatural moieties beyond traditional 20 amino acids. From such hybrid libraries one can rapidly identify ligands that target brain specific transmembrane proteins with high specificity and affinity. This project will focus on the identification of ligands that bind selectively to brain specific transmembrane proteins, the functionalization of materials with these ligands, and the evaluation of these materials for facilitating increased uptake from the microvasculature to the brain parenchyma.