Hepatotoxic mechanisms of anti-HIV- and anti-COVID-19 drugs and substance use disorders

抗 HIV 和抗 COVID-19 药物和物质使用障碍的肝毒性机制

• 批准号: 10684434
• 负责人: CHENG JI
• 金额: $ 39.19万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684434
• 关键词: 2019-nCoV; AGFG1 gene; Acetals; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Alcohol consumption; Alcohols; Animal Model; Anti-HIV Agents; Antiviral Agents; Blood alcohol level measurement; Buprenorphine; Butyric Acids; COVID-19; COVID-19 patient; COVID-19 vaccine; Caring; Cause of Death; Cell Death; Cells; Cellular Stress; Compensation; Coronavirus; Development; Dexamethasone; Digestion; Disease; Dose; Drug Use Disorder; Drug usage; Endopeptidases; Endoplasmic Reticulum; Enzymes; Event; Excision; Experimental Models; FDA approved; Family; Fatty Liver; Functional disorder; Genetic; Golgi Apparatus; HIV; HIV Infections; HIV vaccine; HIV/AIDS; Hepatic; Hepatocyte; Hepatotoxicity; Home; Homeostasis; Hospitalization; Human; Immune response; In Vitro; Individual; Injury; Life; Link; Liver; Liver diseases; Lopinavir; Malignant Neoplasms; Measures; Molecular; Molecular Chaperones; Monomeric GTP-Binding Proteins; Mus; Organelles; Oxidoreductase; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Proteins; Quality of life; Quarantine; Recovery; Regimen; Reporting; Risk; Ritonavir; Role; Signal Transduction; Steatohepatitis; Stress; Substance Use Disorder; Substance abuse problem; Tenofovir; Testing; Therapeutic; Time; Transaminases; Viral; Virus Diseases; Virus Replication; alcohol oxidase; alcohol use disorder; antiretroviral therapy; biological adaptation to stress; catalase; chronic alcohol ingestion; comorbidity; coronavirus disease; drug induced liver injury; efavirenz; endoplasmic reticulum stress; improved; in vivo; liver injury; molecular marker; molnupiravir; nanoparticle; next generation; nirmatrelvir; novel; pandemic disease; prophylactic; rab GTP-Binding Proteins; remdesivir; response; side effect; stress reduction; substance use; tauroursodeoxycholic acid; trafficking; transcriptome sequencing; vaccine development; viral pandemic

Virus infections such as HIV/AIDS and SARS-CoV-2/COVID-19 sicken hundreds of millions of people. The current multiple pandemics have caused unprecedented levels of stress and other life disruptions, which exacerbate substance use disorders, increasing side effects of antiviral drugs and interfering with recovery of individuals suffering from virus infections. Antivirals such as remdesivir, molnupiravir, ritonavir, nirmatrelvir, tenofovir, and darunavir are commonly used to inhibit replication or cell entry for HIV and SARS-CoV-2, thereby inhibiting viral infections. However, some antivirals such as ritonavir of current regimens, especially in combination with other drugs or substance alcohol use, often induced liver injuries causing serious complications. Recently, we have found that remdesivir, ritonavir, and alcohol induce cellular organelle stress, especially endoplasmic reticulum (ER) stress, which is well established not only to cause hepatic cell death but also to compromise immune response leading to a spectrum of liver diseases in a variety of animal models as well as in human patients. Most recently, we discovered with next-generation RNA sequencing that a host protease, RCE1 is a potential off- target of the antiviral drugs. The substrates of RCE1 are limited to a few Rab small GTPase proteins (Rab proteins) with a CaaX motif, which are consequently reduced in the presence of anti-HIV or anti- COVID-19 drugs and reduced much more in drug and alcohol combinations. Because the Rab proteins regulate ER-Golgi trafficking that is essential for cellular organellar homeostasis in the liver, we hypothesize that the antiviral drugs inhibit the host RCE-Rab proteins and induce organelle stress responses that leads to fatty liver injury, and alcohol consumption under stress conditions (e.g., suffering from COVID-19 or frequent quarantine) worsens the drug-induced liver complications. We propose to investigate the pathogenic mechanisms of the RCE-Rab pathway in the antiviral-induced organelle stress and explore pharmaceutical and genetic solutions to mitigate the antiviral drug-induced hepatic injury. Our specific aims are to: (1) validate the mechanistic link of the RCE-Rab pathway with anti-HIV drug and alcohol-induced organelle stress and liver injury, (2) verify whether emerging anti- coronavirus drugs and/or alcohol consumption inhibit the RCE-Rab pathway and induce organelle stress in the liver, (3) explore pharmaceutical and genetic solutions to mitigate the antiviral drug- induced liver injury via testing prophylactic effects of enhanced expression of Rab proteins that compensate the consequence of the antiviral-inhibited host protease, and testing effects of unique enzyme nano-particles that facilitate alcohol removal. Our long-term objectives are to unravel specific pathogenic mechanisms underlying side effects of antivirals so that to improve/modify current antiviral drugs for a better care of the AIDS patients suffering from HIV and SARS-CoV-2 virus infections.

艾滋病毒/艾滋病和SARS-CoV-2/COVID-19等病毒感染使数亿人丧生。 目前的多重流行病造成了前所未有的压力和其他生活中断， 这会加剧物质使用障碍，增加抗病毒药物的副作用，并干扰 病毒感染者的康复。抗病毒药物，如瑞德西韦，莫努匹拉韦， 利托那韦、尼马曲韦、替诺福韦和地瑞那韦通常用于抑制复制或细胞进入， 艾滋病毒和 SARS-CoV-2，从而抑制病毒感染。然而，一些抗病毒药物，如利托那韦， 目前的治疗方案，特别是与其他药物或物质酒精的使用相结合，往往会导致 肝损伤导致严重并发症。最近，我们发现瑞德西韦、利托那韦和 酒精诱导细胞器应激，尤其是内质网应激， 建立不仅导致肝细胞死亡，而且还损害免疫反应，导致 在各种动物模型以及人类患者中的肝脏疾病谱。最近， 我们通过下一代RNA测序发现，宿主蛋白酶RCE 1是一种潜在的关闭， 抗病毒药物的靶点。RCE 1的底物仅限于少数Rab小GT3蛋白 (Rab蛋白质），其因此在抗HIV或抗HIV抗体的存在下被还原。 COVID-19药物和减少更多的药物和酒精组合。因为Rab蛋白 调节ER-高尔基体的运输，这是必要的细胞器在肝脏的稳态，我们 假设抗病毒药物抑制宿主RCE-Rab蛋白并诱导细胞器应激 导致脂肪肝损伤的反应，以及在应激条件下的酒精消耗（例如， 患有COVID-19或频繁隔离）会导致药物引起的肝脏并发症。我们 建议研究RCE-Rab途径在抗病毒诱导的 细胞器压力，并探索药物和基因的解决方案，以减轻抗病毒药物引起的 肝损伤我们的具体目标是：（1）验证RCE-Rab途径与 抗HIV药物和酒精引起的细胞器应激和肝损伤，（2）验证是否出现抗- 冠状病毒药物和/或酒精消耗抑制RCE-Rab途径并诱导细胞器 肝脏的压力，（3）探索药物和遗传解决方案，以减轻抗病毒药物- 通过检测Rab蛋白表达增强的预防作用诱导肝损伤， 补偿抗病毒抑制宿主蛋白酶的后果，并测试独特的效果 促进酒精去除的酶纳米颗粒。我们的长期目标是找出 抗病毒药物副作用的致病机制 为更好地照顾艾滋病患者的艾滋病毒和SARS-CoV-2病毒感染的药物。