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p -糖蛋白(Pgp)-的深入，分子水平的理解