Inhibition or evasion of P-glycoprotein-mediated drug transport

抑制或逃避 P-糖蛋白介导的药物转运

• 批准号: 10568723
• 负责人: Qinghai Zhang
• 金额: $ 51.02万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568723
• 关键词: ABCB1 gene; ATP Hydrolysis; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Address; Adverse effects; Affect; Binding; Binding Sites; Biochemical; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Cardiovascular Diseases; Cell membrane; Cells; Charge; Chemicals; Clinical; Complement; Complex; Coupled; Cryoelectron Microscopy; Data; Development; Disease; Documentation; Drug Efflux; Drug Industry; Drug Interactions; Drug Kinetics; Drug Transport; Epilepsy; Evaluation; Funding; Goals; HIV; Human; Hydrophobicity; Intestines; Investigational Drugs; Kidney; Lead; Learning; Libraries; Ligands; Lipid Bilayers; Literature; Liver; Malignant Neoplasms; Mediating; Membrane Proteins; Modality; Modification; Molecular; Molecular Conformation; Multi-Drug Resistance; Mutagenesis; Pharmaceutical Preparations; Play; Positioning Attribute; Predisposition; Process; Property; Rationalization; Reagent; Resolution; Role; Series; Structure; Testing; Transmembrane Domain; Treatment Efficacy; United States Food and Drug Administration; Vacuum; antagonist; chemical synthesis; clinical development; clinical efficacy; clinically significant; design; drug development; drug discovery; drug efficacy; efflux pump; glycoprotein structure; improved; indium arsenide; inhibitor; insight; novel; novel strategies; novel therapeutics; pharmacologic; scaffold; screening; structural biology

The overarching goal of this project is to obtain a deep, molecular-level understanding of P-glycoprotein (Pgp)- mediated drug transport and efflux inhibition. Pgp belongs to a very important class of ATP-binding cassette (ABC) transporters that transport substrates out of cells using the energy of ATP hydrolysis. One of the truly remarkable features of Pgp is its unusually broad polyspecificity. Pgp functions like a hydrophobic vacuum cleaner, transporting diverse molecules including many clinically useful drugs that partition into the lipid bilayer. Pgp is known to be a key determinant of the bioavailability, pharmacokinetics, and clinical efficacy of drugs in humans. Pgp also causes cellular multidrug resistance, hindering the treatment of many diseases. Because of the potential adverse effects of Pgp efflux on drugs, the US Food and Drug Administration mandates documentation of drug interactions with Pgp for approval of any new drug. Evasion or inhibition of Pgp without compromising therapeutic efficacy has been a major goal of the pharmaceutical industry, which, however, is seriously hindered by the lack in the fundamental understanding of the polyspecific Pgp-drug interactions. Our long-term goal in studying Pgp/drug interactions is to facilitate the development and discovery of new drugs that either inhibit or evade Pgp efflux. Towards this end, we propose three independent but related specific aim studies for this project, with each addressing a key question closely related to drug development. In Aim 1, we will discover bona fide Pgp antagonists for mechanistic studies. We note that many widely studied Pgp inhibitors compete with drugs for Pgp transport. We envision the discovery of novel, nonsubstrate Pgp antagonists displaying distinct properties from the known inhibitors, which is crucial to Pgp inhibition mechanistic studies and for the development of better drugs to inhibit Pgp. In Aim 2, we will interrogate how Pgp discriminates transport substrates and inhibitors. We have formulated a novel hypothesis that the two halves of Pgp may play different roles in Pgp transport and inhibition, based on several preliminary studies. We will further investigate this hypothesis by covalently attaching ligands to different binding sites in Pgp and then characterizing Pgp structure and activity to find correlations. In Aim 3, we propose to rationalize chemical strategies to modify drugs to evade Pgp transport. We will carry out systematic chemical modifications on specific ligands for Pgp structural and activity relationship studies to learn the basic chemical principles underlying Pgp-drug interactions. Our aim studies for Pgp incorporate novel chemical designs complemented by in-depth activity and structural studies. We have collected strong preliminary data to demonstrate the feasibility and novelty of each Aim study. Our approach is quite unique and will offer unprecedented insights into the complex interactions of drugs with Pgp, thus having a significant impact on drug discovery.

该项目的总体目标是获得对P-糖蛋白（PGP） - 介导的药物转运和外排抑制。 PGP属于非常重要的ATP结合盒 （ABC）使用ATP水解的能量将底物从细胞中输出的转运蛋白。真正的 PGP的显着特征是其异常广泛的多元特异性。 PGP像疏水真空一样起作用 清洁剂，运输多种分子，包括许多临床上有用的药物，可分配到脂质双层中。 已知PGP是药物在药物中的生物利用度，药代动力学和临床功效的关键决定因素 人类。 PGP还会引起细胞多药耐药性，阻碍了许多疾病的治疗。由于 PGP外排对药物的潜在不利影响，美国食品和药物管理局要求 药物相互作用与PGP的文档以批准任何新药。没有PGP的逃避或抑制 损害治疗功效一直是制药行业的主要目标，但是 严重阻碍了对多性PGP-prug相互作用的基本理解。我们的 研究PGP/药物相互作用的长期目标是促进开发和发现新药 抑制或逃避PGP外排。为此，我们提出了三个独立但相关的特定目标 该项目的研究，每个项目都解决了与药物开发密切相关的关键问题。在AIM 1中，我们 将发现真正的PGP拮抗剂进行机械研究。我们注意到，许多广泛研究的PGP抑制剂 与药物竞争PGP运输。我们设想了新颖的无底物PGP拮抗剂的发现 显示出已知抑制剂的不同特性，这对于PGP抑制机理研究至关重要 为了开发更好的药物抑制PGP。在AIM 2中，我们将询问PGP如何区分运输 底物和抑制剂。我们已经提出了一个新的假设，即PGP的两半可能发挥不同 基于几项初步研究，在PGP运输和抑制中的作用。我们将进一步调查 通过共价连接配体在PGP中的不同结合位点的假设，然后表征PGP结构 和活动以找到相关性。在AIM 3中，我们建议将化学策略合理化以修改药物以逃避 PGP运输。我们将对PGP结构和 活动关系研究以学习PGP-grug相互作用的基本化学原理。我们的目标 PGP的研究结合了新型化学设计，与深度活性和结构研究相辅相成。 我们已经收集了强大的初步数据，以证明每个目标研究的可行性和新颖性。我们的 方法非常独特，将为药物与PGP的复杂相互作用提供前所未有的见解， 因此，对药物发现产生了重大影响。