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多肽模拟物。然而，由于 它们通过生物屏障(如肠道)的低渗透性 粘膜、脑内皮细胞)和它们被清除的倾向 肝脏和胆汁中消除的多肽模拟物已经很难 发展成为治疗剂。例如，一般的多肽模拟物 表现出极低的口服血药利用率，这可归因于低 肠粘膜通透性和/或快速首过 由肝脏清除。此外，即使在多肽模拟物 通过肠外途径(如静脉注射)给药，他们在 一般被肝脏迅速清除，往往不能进入 重要的靶器官(如大脑)。因此，总体目标是 这项研究项目的目的是阐明不同的生物同种异构体对 多肽键对生物屏障通透性的影响 肠粘膜和血脑屏障(BBB)及其作用 这些结构改变在第一次通过时就被肝脏清除了。 排出到胆汁中。这些目标将通过以下方式实现 合成一系列常用的二肽和三肽 多肽键的生物异构体。然后我们将确定他们的总体情况 肠渗透的通透性及其途径(S) 粘膜，使用体外细胞培养模型(Caco-2)和原位大鼠 肠道灌流模型，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 大鼠原位脑灌流模型。实验将被设计成 阐明被动途径和载体介导途径的作用 (例如，肠粘膜中的肽转运体)的通量和TO 确定其渗透性是否受其底物属性的限制 对于顶部极化的外流机制(P-糖蛋白)，存在于 肠粘膜和血脑屏障。还将进行实验，以 确定这些多肽模拟物的肝脏清除特性 原位灌流大鼠肝脏模型和分离的肝细胞。实验 将旨在阐明被动型和被动型的贡献 载体介导的途径(例如，牛磺胆酸钠共转运体)。 基于这个项目的结果，关于“结构”的知识 常用的多肽生物异构体的运输关系将是 即将到来。这一信息应该可以让药物化学家同时做到这两点 “合理的药物输送”(侧重于跨越生物障碍的运输) 和《合理的药物设计》(侧重于药理靶点) 最终将导致多肽模拟物的设计 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.