Metabolic basis for lipid abnormality with anti-HIV tenofovir prodrugs

抗HIV替诺福韦前药脂质异常的代谢基础

• 批准号: 10026409
• 负责人: Bingfang Yan
• 金额: $ 20.09万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026409
• 关键词: Acquired Immunodeficiency Syndrome; Alcohol abuse; Alcohols; Amides; Anti-HIV Agents; Applications Grants; Biological Assay; Carboxylesterase 1; Cells; Cessation of life; Clinical Research; Data; Development; Diet; Diphosphates; Dose; Drug Interactions; Enzymes; Esters; Ethanol; Fatty Liver; Foundations; Genetic Polymorphism; Genetic Transcription; HIV; HIV therapy; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Hepatitis Viruses; Hepatomegaly; Hepatotoxicity; Human; Hydrolysis; Kidney; Knock-out; Knowledge; Laboratories; Light; Lipids; Liver; Medicine; Metabolic; Monitor; Mus; Parents; Patients; Permeability; Pharmaceutical Preparations; Positioning Attribute; Process; Prodrugs; Production; Risk; Role; Safety; Sampling; Specific qualifier value; System; Tenofovir; Testing; Therapeutic; Time; To specify; Toxic effect; Variant; Vertebral column; Virus Diseases; Work; absorption; anti-hepatitis B; bone; carboxylesterase; chronic liver disease; clinically relevant; clinically significant; co-infection; design; global health; individual variation; innovation; inter-individual variation; interest; liver xenograft; mortality; overexpression; stem; transcriptome

Human immunodeficiency virus (HIV) continues to be a major global health issue. Remarkably, AIDS-related death (acquired immunodeficiency syndrome) has decreased in recent years. Alarmingly, chronic liver diseases have become major causes of mortality among HIV patients, largely due to hepatotoxicity of anti-HIV drugs, widespread alcohol abuse and coinfection of hepatitis viruses such as hepatitis B virus (HBV). Tenofovir disoproxil and tenofovir alafenamide are major anti-HIV medicines and also used to treat HBV infection. Both tenofovir drugs are ester prodrugs and hydrolytically activated, primarily by carboxylesterases (CES), an enzyme system with large individual variability due to expression and/or genetic polymorphism. Tenofovir prodrugs are generally well tolerated, but have been associated with renal/bone toxicity and steatosis. Our Preliminary Study has shown that tenofovir prodrugs increased lipid retention and tenofovir alafenamide underwent transesterification by carboxylesterase-1 in the presence of ethanol. The central hypo- thesis of the project is that carboxylesterases determine therapeutic activation and steatotic potential of tenofovir prodrugs through hydrolysis, transesterification and inhibition. The Specific Aims are: (1) to signify catalytic actions of carboxylesterases for activation and safety, and (2) to investigate the steatotic potential of tenofovir prodrugs. A large number of human samples (>300) will be assayed for the hydrolysis of tenofovir prodrugs in the presence and absence of ethanol or a commonly coadministered drug to ascertain the interplay of hydrolytic activation over transesterification and inhibition. The role of carboxylesterases in the interplay will be confirmed in cells selectively knocked out or overexpressing a carboxylesterase. To specify the steatotic potential of tenofovir prodrugs and their steatotic interaction with ethanol, hepatically xenografted mice with these lines will be dosed with tenofovir alafenamide and fed with ethanol-containing diet, and the steatosis will be monitored. In addition, transcriptome of tenofovir prodrugs will be determined as a function of hydrolysis to shed light on how tenofovir prodrugs (not their hydrolytic metabolite) are engaged in steatotic development. The focus on the carboxylesterase system, related to anti-HIV/HBV therapy, is conceptually innovative and clinically significant. Overall, the scientific premise is strong, the clinical relevance is high, and many studies (e.g., steatosis-favoring transcriptome) will have lasting and broad impact. Finally, this laboratory has a long standing interest in carboxylesterases. Decades of work position us well to progress this project.

人类免疫缺陷病毒（HIV）仍然是一个主要的全球健康问题。值得注意的是，与艾滋病相关 死亡（获得性免疫缺陷综合症） 近年来有所减少。令人担忧的是，慢性肝病 疾病已成为艾滋病毒患者死亡的主要原因，很大程度上是由于抗艾滋病毒药物的肝毒性 药物、普遍酗酒以及乙型肝炎病毒 (HBV) 等肝炎病毒的合并感染。 替诺福韦二吡呋酯和替诺福韦艾拉酚胺是主要的抗 HIV 药物，也用于治疗 HBV 感染。两种替诺福韦药物都是酯前药，主要由羧酸酯酶水解激活 （CES），一种由于表达和/或遗传多态性而具有较大个体变异性的酶系统。 替诺福韦前药通常耐受性良好，但与肾/骨毒性和 脂肪变性。我们的初步研究表明，替诺福韦前药增加了脂质保留，替诺福韦 艾拉酚胺在乙醇存在下通过羧酸酯酶 1 发生酯交换反应。中枢低 该项目的论文是，羧酸酯酶决定治疗激活和脂肪变性潜力 替诺福韦前药通过水解、酯交换和抑制作用产生。具体目标是： (1) 表示 羧酸酯酶的催化活性和安全性，以及（2）研究脂肪变性的潜力 替诺福韦前药。将检测大量人体样本（>300）的替诺福韦水解情况 在存在和不存在乙醇或常用药物的情况下进行前药以确定相互作用 水解活化超过酯交换和抑制。羧酸酯酶在相互作用中的作用 在选择性敲除或过表达羧酸酯酶的细胞中得到证实。指定脂肪变性 替诺福韦前药的潜力及其与乙醇的脂肪变性相互作用，肝异种移植小鼠 这些品系将服用替诺福韦艾拉酚胺并喂食含乙醇的饮食，脂肪变性将 被监控。此外，替诺福韦前药的转录组将被确定为水解的函数 阐明替诺福韦前药（不是其水解代谢物）如何参与脂肪变性的发展。 对与抗 HIV/HBV 治疗相关的羧酸酯酶系统的关注在概念上是创新的， 有临床意义。总体而言，科学前提强，临床相关性高，研究较多 （例如，有利于脂肪变性的转录组）将产生持久和广泛的影响。最后，这个实验室有很长的 对羧酸酯酶的长期兴趣。数十年的工作使我们能够很好地推进这个项目。