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: 10254403
• 负责人: Bingfang Yan
• 金额: $ 24.3万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254403
• 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.

人体免疫机能丧失病毒（艾滋病毒）仍然是一个重大的全球健康问题。值得注意的是， 死亡（获得性免疫缺陷综合症） 近年来有所下降。令人担忧的是，慢性肝病 疾病已经成为HIV患者死亡的主要原因，主要是由于抗HIV药物的肝毒性。 药物、广泛的酒精滥用和肝炎病毒如B型肝炎病毒（HBV）的合并感染。 替诺福韦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类前药，主要通过羧酸酯酶水解活化 (CES)由于表达和/或遗传多态性而具有大的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/骨毒性相关， 脂肪变性我们的初步研究表明，替诺福韦前药增加脂质潴留和替诺福韦 阿拉芬胺在乙醇存在下通过羧酸酯酶-1进行酯交换。中央卫生- 该项目的论点是，羧酸酯酶决定治疗激活和脂肪变性的潜力， 替诺福韦前体药物通过水解、酯交换和抑制作用。具体目的是：（1）表示 羧酸酯酶的活化和安全性的催化作用，以及（2）研究 替诺福韦前药。将对大量人体样本（>300）进行替诺福韦水解检测 在存在和不存在乙醇或通常共同施用的药物的情况下， 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将 在选择性敲除或过表达羧酸酯酶的细胞中得到证实。为了说明脂肪变性 替诺福韦前药的潜力及其与乙醇的脂肪变性相互作用， 这些细胞系将给予替诺福韦艾拉酚胺并喂食含乙醇的饮食， 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， 揭示了替诺福韦前药（不是它们的水解代谢物）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，科学性强，临床相关性高， (e.g.,脂肪变性倾向转录组）将产生持久和广泛的影响。最后，这个实验室有一个很长的 对羧酸酯酶有兴趣。几十年的工作使我们能够很好地推进这个项目。