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首页> 外文学位 >Inhibitor and Substrate Requirements of Sodium Taurocholate Cotransporting Polypeptide and Its Application to Liver Targeting.
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Inhibitor and Substrate Requirements of Sodium Taurocholate Cotransporting Polypeptide and Its Application to Liver Targeting.

机译：牛磺胆酸钠共转运多肽的抑制剂和底物要求及其在肝靶向中的应用。

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摘要

Human sodium taurocholate cotransporting polypeptide (NTCP) is the bile acid transporter that is also involved in hepatitis virus infection, drug disposition and prodrug targeting. Identification of NTCP inhibitors and substrates may help to treat hepatitis B, reduce NTCP mediate drug interaction and develop prodrugs to achieve liver specific drug delivery. However the understanding of structure-activity relationship of NTCP is very limited. One objective of the work in this dissertation is to fill this gap by exploring the inhibitor and substrate requirements of human NTCP. The other objective is to utilize NTCP to achieve liver targeting of ribavirin in order to reduce its off-target side effects. A common feature pharmacophore, a quantitative pharmacophore and a Bayesian model were developed and validated using FDA approved drugs to elucidate the inhibitor requirements of human NTCP. All these in silico models were able to predict NTCP inhibitors. Twenty seven novel NTCP inhibitors were identified which cover variety of therapeutic classes.;The substrate requirements of NTCP were studied using native bile acids and bile acid analogs, suggesting a role of hydroxyl pattern and steric interaction in NTCP binding and translocation. One common feature pharmacophore was developed for NTCP substrates, which was used to search a database of FDA approved drugs. Among the retrieved drugs, irbesartan and losartan were identified as novel NTCP substrates, indicating a potential role of NTCP in drug disposition.;In order to reduce ribavirin off-target side effects, ribavirin-L-Val-GCDCA was developed as a prodrug to target NTCP. In vitro uptake and metabolic studies indicated that the prodrug was taken up by NTCP, released ribavirin in the mouse live S9 fraction and reduced ribavirin accumulation in red blood cells (RBC). An in vivo study in mice showed that ribavirin-L-Val-GCDCA provided almost the same ribavirin exposure in the liver as ribavirin administration, but with about 2-fold less exposure of ribavirin in RBC, plasma, and kidney, suggesting that ribavirin-L-Val-GCDCA has the potential to achieve greater liver specific delivery of ribavirin.;Overall, the work carried out in this dissertation will aid to identify human NTCP inhibitors and substrates, as well as a prodrug design for liver targeting.
机译：人牛磺胆酸钠共转运多肽（NTCP）是胆汁酸转运蛋白，也参与肝炎病毒感染，药物处置和前药靶向。 NTCP抑制剂和底物的鉴定可能有助于治疗乙型肝炎，减少NTCP介导药物相互作用并开发前药以实现肝脏特异性药物递送。然而，对NTCP的结构-活性关系的理解非常有限。本文工作的一个目标是通过探索人类NTCP的抑制剂和底物需求来填补这一空白。另一个目的是利用NTCP来实现利巴韦林的肝脏靶向，以减少其脱靶副作用。使用FDA批准的药物阐明人类NTCP的抑制剂要求，开发并验证了通用特征药效基团，定量药效基团和贝叶斯模型。所有这些计算机模型均能够预测NTCP抑制剂。鉴定出二十七种新颖的NTCP抑制剂，它们涵盖了各种治疗类别。使用天然胆汁酸和胆汁酸类似物研究了NTCP的底物要求，表明了羟基模式和空间相互作用在NTCP结合和转运中的作用。开发了一种用于NTCP底物的通用特征药效团，该药效团用于搜索FDA批准药物的数据库。在回收的药物中，厄贝沙坦和氯沙坦被鉴定为新型NTCP底物，表明NTCP在药物处置中具有潜在作用。为了减少利巴韦林的脱靶副作用，开发了利巴韦林-L-Val-GCDCA作为前体药物目标NTCP。体外吸收和代谢研究表明，NTCP吸收了前药，在小鼠活S9组分中释放了病毒唑，并减少了病毒唑在红细胞（RBC）中的积累。在小鼠体内进行的一项研究表明，利巴韦林-L-Val-GCDCA在肝脏中提供的利巴韦林暴露与利巴韦林给药几乎相同，但在红细胞，血浆和肾脏中利巴韦林的暴露少约2倍，这表明利巴韦林- L-Val-GCDCA有可能实现更大的利巴韦林在肝脏中的特异性传递。总体而言，本论文的工作将有助于鉴定人NTCP抑制剂和底物，以及针对肝脏靶向的前药设计。

著录项

  • 作者

    Dong, Zhongqi.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Pharmaceutical sciences.;Public health.;Epidemiology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 220 p.
  • 总页数 220
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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