Substrate requirements of the bile acid transporter

胆汁酸转运蛋白的底物要求

• 批准号: 7487551
• 负责人: JAMES E POLLI
• 金额: $ 29.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-10 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487551
• 关键词: 3-Dimensional; ASBT protein; Acyclovir; Bile Acid Biosynthesis Pathway; Bile Acids; Biological; Biological Assay; Biological Availability; Biological Models; Biology; Carrier Proteins; Cells; Charge; Chemicals; Chemistry; Classification; Complement; Cultured Cells; Daily; Data; Data Set; Descriptor; Development; Drug Delivery Systems; Evaluation; Gastrointestinal tract structure; Genetic; Glutamic Acid; Goals; Human; In Vitro; Intestines; Kinetics; Knowledge; Lead; Location; Longitudinal Studies; Measures; Mediating; Membrane; Membrane Transport Proteins; Methods; Modeling; Molecular; Molecular Conformation; Nutrient; Oral; Parents; Pattern; Pharmaceutical Preparations; Physiological; Prodrugs; Property; Proteins; Quantitative Structure-Activity Relationship; Rattus; Research; Research Personnel; Resolution; Role; Series; Side; Structure; System; Testing; Time; Xenobiotics; absorption; analog; base; bile acid transporter; carboxylate; design; ileum; in vivo; interdisciplinary approach; molecular modeling; monolayer; novel; programs; protein structure; solute

DESCRIPTION (PROVIDED BY APPLICANT): Several solute carrier proteins (SLC) are expressed in the intestine to absorb nutrients and xenobiotics. In spite of their physiological importance, carrier proteins have not been systematically employed as targets to increase oral drug bioavailability. The current proposal aims to close this gap by focusing on one of the few pharmacologically important transporters in the gastrointestinal tract: the human apical sodium-dependent bile acid transporter (hASBT). hASBT reabsorbs over 12 grams of bile acids daily, suggesting hASBT's tremendous capacity to serve as a drug or prodrug target for absorption. Preliminary data shows that drugs may be conjugated with a bile acid's C-24 carboxylate to yield prodrugs that are translocated by hASBT and increase drug bioavailability. Acyclovir's bioavailability was doubled in rats using a prodrug that targets hASBT. We hypothesize that a systematic structure-activity approach can be used to elucidate the chemistry space of the bile acid's C-24 side chain region that permits bile acid conjugates to be transported by hASBT. The aim of this proposal is to develop a comprehensive and predictive three-dimensional quantitative structure-activity relationship (3D-QSAR) model for the hASBT substrate requirements of bile acid conjugates. 3D-QSAR development will be achieved by synthesizing several congeneric series of bile acid conjugates that systematically span a diverse chemistry space in the C-24 side chain region. Conjugates will be assayed for hASBT-mediated transport and inhibition using in vitro cell culture. A novel molecular modeling approach that considers conformation distribution patterns will be used in 3D-QSAR development. In vivo evaluation of selected bile acid conjugates will be performed in rats, to scale the in vitro 3D-QSAR model to an in vivo 3D-QSAR model. This proposal represents a chemistry-based approach to assess hASBT functioning and complements ongoing biophysical studies. The long-term goal of this research is to use the developed 3D-QSAR model to rationally select parent drugs and their resulting prodrugs for successful hASBT targeting. This systematic and progressive approach will serve as a prototypical method to elucidate the substrate requirements of other solute carrier (SLC) proteins.

描述（申请人提供）：几种溶质载体蛋白（SLC）在肠道中表达，以吸收营养物质和外源性物质。尽管它们的生理重要性，载体蛋白尚未被系统地用作增加口服药物生物利用度的靶标。目前的提案旨在通过关注胃肠道中少数几个重要的转运蛋白之一来缩小这一差距：人类顶端钠依赖性胆汁酸转运蛋白（hASBT）。hASBT每天重吸收超过12克胆汁酸，表明hASBT作为药物或前药吸收靶点的巨大能力。初步数据显示，药物可以与胆汁酸的C-24羧酸酯缀合，以产生通过hASBT移位并增加药物生物利用度的前药。使用靶向hASBT的前药，阿昔洛韦在大鼠中的生物利用度增加了一倍。 我们假设，系统的结构-活性方法可以用来阐明胆汁酸的C-24侧链区，允许胆汁酸共轭物被运输的hASBT的化学空间。本提案的目的是开发一个全面的和预测性的三维定量构效关系（3D-QSAR）模型的胆汁酸结合物的hASBT底物的要求。3D-QSAR的开发将通过合成几个同源系列的胆汁酸缀合物来实现，这些缀合物系统地跨越C-24侧链区域中的不同化学空间。将使用体外细胞培养物测定结合物的hASBT介导的转运和抑制。一种新的分子建模方法，考虑构象分布模式将用于三维定量构效关系的发展。将在大鼠中对选定的胆汁酸结合物进行体内评价，以将体外3D-QSAR模型缩放为体内3D-QSAR模型。该提案代表了评估hASBT功能的基于化学的方法，并补充了正在进行的生物物理研究。 本研究的长期目标是使用开发的3D-QSAR模型来合理选择母体药物及其产生的前药，以成功靶向hASBT。这种系统和渐进的方法将作为一个原型的方法来阐明其他溶质载体（SLC）蛋白质的底物要求。