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）仍然是全球主要的健康问题。值得注意的是，与艾滋病有关 死亡（获得的免疫缺陷综合征） 近年来有所下降。令人震惊的是，慢性肝脏 疾病已成为HIV患者死亡率的主要原因，这主要是由于抗HIV的肝毒性 药物，广泛的酒精滥用以及肝炎病毒（HBV）等肝炎病毒的共同感染。 Tenofovir disoproxil和Tenofovir alafenamide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，主要由羧酸酯酶激活 （CES），一种由于表达和/或遗传多态性而引起的具有较大个性变异性的酶系统。 Tenofovir前药通常具有很好的耐受性，但与肾脏/骨毒性有关 脂肪变性。我们的初步研究表明，Tenofovir前药增加了脂质保留和替诺福韦 在存在乙醇的情况下，Alafenamide通过羧酸酯酶1进行了惯性化。中央低调 该项目的论点是羧酸酯酶确定了治疗激活和脂肪性的潜力 替诺福韦前药通过水解，静脉化和抑制作用。具体目的是：（1）表示 羧酸酯酶激活和安全的催化作用，以及（2）研究 Tenofovir前药。将分析大量的人类样品（> 300）用于替诺福韦的水解 在存在和不存在乙醇或常用的药物的情况下，前药以确定相互作用 水解激活过于静止化和抑制作用。羧酸酯酶在相互作用中的作用将 在选择性敲除或过表达羧酸酯酶的细胞中得到证实。指定臭虫 Tenofovir前药的潜力及其与乙醇的脂肪性相互作用，肝异种移植小鼠与 这些线将用替诺福韦甲酰胺剂量，并添加含有乙醇的饮食，脂肪变性将 被监视。此外，Tenofovir前药的转录组将被确定为水解的函数 阐明了替诺福韦前药（不是其水解代谢物）如何从事脂肪变化的发育。 与抗HIV/HBV疗法有关的羧酸酯酶系统的重点在概念上是创新的，并且 临床意义。总体而言，科学前提很强，临床相关性很高，许多研究 （例如，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 对羧酸酯酶的兴趣。数十年的工作地位我们很高兴地进展。