TRANSPORT CHARACTERISTICS OF PEPTIDE MIMETICS

描述(逐字摘自申请人摘要)：在过去的20年里， 药物化学家已经合成了许多多肽模拟物(例如，HIV蛋白酶 糖蛋白(GP)IIb/IIIa受体拮抗剂) 治疗适应症(例如，抗病毒(艾滋病)、抗血栓药物)。这些 多肽模拟物包含使其稳定为水解物的结构特征 代谢途径和/或赋予它们独特的结构特征， 优化它们与其大分子靶标的相互作用(例如， 酰胺键的生物同位异构体，转位模拟)。然而，由于他们的贫穷 生物制药特性(例如，通过肠道的低渗透 粘膜和肝脏的高清晰度)，多肽模拟物通常表现得较少 比最佳口服生物利用度更好。即使在给予多肽模拟物的情况下 在非肠道情况下，它们通常会被肝脏迅速清除，而不是 进入重要的目标区域(例如，大脑)。因此，本研究 计划的重点是阐明不同的酰胺键生物等位体的影响 构象约束对多肽模拟物的渗透 通过肠粘膜和血脑屏障(BBB)，并对其 肝脏第一次通过检查。特别感兴趣的是那些 涉及转运蛋白，它要么促进穿透 肠粘膜(例如，寡肽转运体)或限制渗透 穿过肠粘膜和血脑屏障，促进肝脏的清除 (例如，多药耐药相关蛋白(MDR1)和多药耐药 相关蛋白(MRP1、MRP2)。这项研究的主要目标是 下一个资助期的计划是：(1)阐明结构-运输 一系列常用的模型肽模拟物之间的关系 生物等位基因和外排转运蛋白的构象限制(MDR1， MRP1、MRP2)和寡肽转运体；以及(2)确定 这些转运蛋白对体内底物活性的影响 治疗性多肽模拟物(如HIV)的生物药剂学特性 蛋白酶抑制剂、GPIIb/IIIa受体拮抗剂)。《知识》 这项研究计划将有助于药物化学家 合理设计具有改进生物药学特性的多肽模拟物。

DESCRIPTION (verbatim from applicant's abstract): Over the past 20 years, medicinal chemists have synthesized many peptide mimetics (e.g., HIV protease inhibitors, glycoprotein (gp) IIb/IIIa receptor antagonists) with novel therapeutic indications (e.g., antiviral (AIDS), antithrombotic agents). These peptide mimetics contain structural features that stabilize them to hydrolytic pathways of metabolism and/or endow them with unique structural features that optimize their interactions with their macromolecular target (e.g., bioisosteres of amide bonds, turn mimetics). However, because of their poor biopharmaceutical properties (e.g., low permeation through the intestinal mucosa and high clearance by the liver), peptide mimetics often exhibit less than optimal oral bioavailability. Even when peptide mimetics are administered parenterally, they are in general rapidly cleared by the liver and tend not to gain access to important target areas (e.g., brain). Therefore, this research program is focused on elucidating what effects various amide bond bioisosteres and conformational constraints have on the permeation of peptide mimetics through the intestinal mucosa and the blood-brain barrier (BBB) and on their first pass clearance by the liver. Of particular interest are pathways that involve transporter proteins which either facilitate permeation across the intestinal mucosa (e.g., oligopeptide transporter) or restrict permeation across the intestinal mucosa and the BBB and facilitate clearance by the liver (e.g., multidrug resistance associated protein (MDR1) and multidrug resistance associated proteins (MRP1, MRP2)). The primary objectives of this research program for the next grant period are: (1) to elucidate the structure-transport relationships for a series of model peptide mimetics containing commonly used bioisosteres and conformational constraints with the efflux transporters (MDR1, MRP1, MRP2) and with the oligopeptide transporter; and (2) to determine what impact substrate activity for these transporters have on the in vivo biopharmaceutical properties of therapeutic peptide mimetics (e.g., HIV protease inhibitors, gpIIb/IIIa receptor antagonsits). The knowledge forthcoming from this research program should help medicinal chemists to rationally design peptide mimetics with improved biopharmaceutical properties.