Substrate requirements of the bile acid transporter

胆汁酸转运蛋白的底物要求

• 批准号: 7120636
• 负责人: JAMES E POLLI
• 金额: $ 27.26万
• 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/7120636
• 关键词: biophysics; chemical conjugate; chemical kinetics; chemical models; chemical synthesis; cholanate compound; computer simulation; high performance liquid chromatography; laboratory rat; membrane transport proteins; model design /development; pharmacokinetics; prodrugs; tissue /cell culture

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，以吸收营养和外源物质。尽管载体蛋白具有重要的生理意义，但尚未被系统地用作提高口服药物生物利用度的靶点。目前的提案旨在通过关注胃肠道为数不多的药理上重要的转运体之一：人心尖钠依赖胆汁酸转运体(HASBT)来弥合这一差距。HASBT每天重新吸收超过12克胆汁酸，这表明HASBT作为药物或前药吸收靶点的巨大能力。初步数据显示，药物可能与胆汁酸的C-24羧酸盐结合，产生可通过hASBT转运的前药，从而提高药物的生物利用度。使用一种针对hASBT的前药，阿昔洛韦在大鼠身上的生物利用度翻了一番。 我们假设一个系统的结构-活性方法可以用来阐明胆汁酸的C-24侧链区域的化学空间，该区域允许胆汁酸偶联物通过hASBT运输。该建议的目的是开发一个全面的和可预测的三维定量构效关系(3D-QSAR)模型，用于预测胆汁酸结合物的hASBT底物需求。3D-QSAR的开发将通过合成几个同类系列的胆汁酸连接物来实现，这些连接物系统地跨越C-24侧链区域的不同化学空间。结合物将通过体外细胞培养来检测hASBT介导的转运和抑制作用。一种新的考虑构象分布模式的分子建模方法将被用于3D-QSAR的开发。选定的胆汁酸结合物将在大鼠身上进行体内评估，以将体外3D-QSAR模型扩展到体内3D-QSAR模型。这一建议代表了一种基于化学的方法来评估hASBT的功能，并补充了正在进行的生物物理研究。 本研究的长期目标是利用开发的3D-QSAR模型合理地选择母体药物及其所产生的前药，以实现成功的hASBT靶向。这种系统和渐进的方法将作为一种典型的方法来阐明其他溶质载体(SLC)蛋白质的底物要求。