TRANSPORT CHARACTERISTICS OF PEPTIDE MIMETICS

通过合理的药物设计，药物化学家已经合成了许多 具有新的治疗潜力的肽模拟物。但由于 它们通过生物屏障的低渗透性（例如，肠 粘膜、脑内皮细胞）以及它们被血管内皮细胞清除的倾向。 肝脏和消除在胆汁中，肽模拟物一直难以 发展成为治疗剂。例如，肽模拟物通常 表现出极低的口服生物利用度， 通过肠粘膜的渗透性和/或快速首过 肝脏清除。此外，即使当肽模拟物被 通过肠胃外途径给药（例如，静脉注射），它们在 一般快速清除肝脏和往往无法获得访问 重要的靶器官（例如，脑）。因此，总体目标 这项研究项目的目的是阐明各种生物电子等排体 通过生物屏障的渗透性 对肠粘膜和血脑屏障（BBB）有什么影响 这些结构修饰在第一次通过时被肝脏清除 并消除到胆汁中。这些目标将通过以下方式实现： 合成了一系列含有常用的二肽和三肽， 肽键的生物电子等排体。然后我们将确定他们的整体 渗透性及其通过肠的渗透途径 粘膜，使用体外细胞培养模型（Caco-2）和原位大鼠 肠灌注模型，并通过血脑屏障，使用体外细胞 培养模型（培养的牛脑微血管内皮细胞）和 原位大鼠脑灌注模型。实验将被设计为 阐明被动和载体介导途径的作用 (e.g.,肠粘膜中的肽转运蛋白）的通量和 确定它们的渗透性是否受到它们的基底性质的限制 对于存在于细胞中的顶端极化外排机制（p-糖蛋白）， 肠粘膜和血脑屏障。还将进行实验， 测定这些肽模拟物的肝清除特性， 原位灌注大鼠肝脏模型和分离的肝细胞。实验 将被设计来阐明两个被动和 载体介导的途径（例如，牛磺胆酸钠共转运蛋白）。 根据该项目的结果， 通常使用的肽生物电子等排体的“运输”关系将是 即将到来。这些信息应该允许药物化学家做到这两点 “合理给药”（侧重于跨生物屏障转运） 和“合理药物设计”（侧重于药理学靶点）， 将最终导致肽模拟物的设计， 作为临床药物开发。

Through rational drug design, medicinal Chemists have synthesized many peptide mimetics with novel therapeutic potential. However, because of their low permeability through biological barriers (e.g., intestinal mucosa, brain endothelial cells) and their propensity to be cleared by the liver and eliminated in the bile, peptide mimetics have been difficult to develop as therapeutic agents. For example, peptide mimetics in general exhibit extremely low oral bloavailability which can be attributed to low permeability through the intestinal mucosal and/or rapid first pass clearance by the liver. In addition, even when peptide mimetics are administered via a parenteral route (e.g., intravenous), they are in general rapidly cleared by the liver and tend not to gain access to important target organs (e.g., brain). Therefore, the overall objectives of this research project are to elucidate what effects various bioisosters of the peptide bond nave on permeability through biological barriers like the intestinal mucosa and the blood brain barrier (BBB) and what effects these structural modifications have on first pass clearance by the liver and elimination into the bile. These objectives will be accomplished by synthesizing a series of di and tripeptides containing commonly used bioisosters of the peptide bond. We will then determine their overall permeability and their pathway(s) of permeation through the intestinal mucosa, using an in vitro cell culture model (Caco-2) and an in situ rat intestinal perfusion model, and through the BBB, using an in vitro cell culture model (cultured bovine brain microvessel endothelial cells) and an in situ rat brain perfusion model. Experiments will be designed to elucidate the contribution of both passive and carrier-mediated pathways (e.g., peptide transporter in the intestinal mucosa) of flux and to determine if their permeability is limited by their substrate properties for an apically polarized efflux mechanism (p-glycoprotein) present in the intestinal mucosa and the BBB. Experiments will also be conducted to determine the liver clearance properties of these peptide mimetics using an in situ perfused rat liver model and isolated hepatocytes. Experiments will be designed to elucidate the contributions of both passive and carrier-mediated Pathways (e.g., sodium taurocholate co-transporters). Based on the results of this project, knowledge about the "structure transport" relationships for commonly used peptide bioisosters will be forthcoming. This information should allow medicinal chemists to do both "rational drug delivery" (focused on transport across biological barriers) and "rational drug design" (focused on the pharmacological target) which will ultimately lead to the design of peptide mimetics that can be developed as clinical agents.