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(艾滋病毒)仍然是一个重大的全球健康问题。值得注意的是，与艾滋病相关的 死亡(获得性免疫缺陷综合征) 近年来有所下降。令人担忧的是，慢性肝脏 疾病已成为艾滋病毒患者死亡的主要原因，主要是由于抗艾滋病毒的肝脏毒性。 吸毒、普遍酗酒以及乙肝病毒(乙肝)等肝炎病毒的混合感染。 替诺福韦和替诺福韦丙氨酰胺是主要的抗艾滋病毒药物，也用于治疗乙肝病毒。 感染。替诺福韦和替诺福韦都是酯前药，主要由羧酸酯酶水解性激活。 (CES)，一种由于表达和/或遗传多态而具有较大个体变异性的酶系统。 替诺福韦前体药物一般耐受性良好，但与肾/骨毒性和 脂肪变性。我们的初步研究表明，替诺福韦前体药物增加了脂质滞留和替诺福韦 在乙醇存在下，丙氨酰胺通过羧酸酯酶-1进行了酯交换反应。中央次声- 该项目的论文是，羧酸酯酶决定了治疗活性和脂肪变性的潜力。 替诺福韦前体药物通过水解、酯交换和抑制。具体目标是：(1)寓意 羧酸酯酶的激活和安全性的催化作用，以及(2)研究脂肪变性的可能性 替诺福韦前体药物。大量人体样本(&gt；300)将被检测为替诺福韦的水解物 在有无乙醇或共同给药的情况下的前药以确定相互作用 水解性激活胜于酯交换和抑制。羧酸酯酶在相互作用中的作用将 在选择性地敲除或过度表达羧酸酯酶的细胞中得到证实。要指定脂肪变性 替诺福韦前药的潜力及其与乙醇的脂肪变性相互作用 这些品系将服用替诺福韦丙氨酰胺，并喂以含乙醇的饮食，脂肪变性将 被监视。此外，替诺福韦前体药物的转录组将作为水解的函数被确定为 阐明替诺福韦前体药物(而不是其水解物)如何参与脂肪变性的发展。 与抗艾滋病毒/乙肝治疗相关的羧酸酯酶系统的重点是概念上的创新和 具有重要的临床意义。总体而言，科学前提很强，临床相关性很高，许多研究 (例如，有利于脂肪变性的转录组)将产生持久和广泛的影响。最后，这个实验室有很长一段时间 对羧酸酯酶的长期兴趣。几十年的工作使我们能够很好地推进这项工程。