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Effects of SARS-CoV-2 Antiviral Ribonucleoside Analogues on Mitochondrial DNA

SARS-CoV-2 抗病毒核糖核苷类似物对线粒体 DNA 的影响

基本信息

批准号：
10448062
负责人：
Alicia M Pickrell
金额：
$ 24.77万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-27 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448062
关键词：
2019-nCoV AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Affect Age Aging American Antibiotics Antiviral Agents Antiviral Therapy Appearance Biochemical Biological Assay Biology COVID-19 COVID-19 impact COVID-19 patient COVID-19 treatment COVID-19 vaccination COVID-19 vaccine Cardiac Cardiac development Cell Culture Techniques Cells Chemicals Chronic Clinical Trials Communities Costs and Benefits DNA DNA Damage DNA Mutational Analysis DNA Sequence Alteration DNA analysis DNA biosynthesis Developing Countries Echocardiography Emergency Situation Enzymes Epidemic Evaluation Exposure to FDA approved Functional disorder Future Generations Genetic Transcription Health Hepatitis C Histopathology Hospitalization In Situ Individual Infection Infection Control Ionophores Lasers Lead Mediation Medical Microscopy Mitochondria Mitochondrial DNA Myopathy Nature Nucleosides Nucleotides Outcome Oxidative Phosphorylation Patients Pharmaceutical Preparations Pharmacotherapy Phase II/III Clinical Trial Physicians Physiology Positioning Attribute Pre-Clinical Model Preclinical Testing Proteins RNA replication Reporting Research Research Personnel Resistance Respiratory Disease Ribonucleosides Risk Rodent Rodent Model SARS-CoV-2 antibody SARS-CoV-2 antiviral SARS-CoV-2 infection Safety Severity of illness Sex Differences Testing Time Tissues Toxic effect Toxicology Vaccination Vaccines Variant Viral Viral Load result Virus Diseases Virus Replication Work Zidovudine age difference age group aged analog antiviral nucleoside analog combat coronavirus disease coronavirus treatment exposed human population in vivo infection rate mature animal mitochondrial DNA mutation mitochondrial dysfunction mortality negative affect next generation sequencing novel nucleoside analog pandemic disease particle patient population pre-clinical premature prevent remdesivir screening sex side effect treatment response vaccine hesitancy viral RNA young adult

项目摘要

PROJECT SUMMARY Antiviral nucleoside analogues are a type of broad-spectrum medication used to prevent viral replication. Only one FDA approved treatment for COVID-19 is a nucleoside analogue and was used under FDA emergency directive to reduce hospitalization times to treat patients infected with the SARS-CoV-2. However, in the past, FDA approved antiviral ribonucleoside analogues used to control infection during the US HIV/AIDS epidemic were shown years later to cause mitochondrial DNA mutations, mitochondrial dysfunction, myopathies, and cause chronic side effects to treated patients. This proposal addresses whether these novel antiviral ribonucleoside analogues (Remdesivir) currently the only FDA approved mediation or (N4-Hydroxycytidine) in Phase II/III clinical trials for COVID-19 affect mitochondrial DNA and mitochondrial function causing cellular and tissue dysfunction. This proposal will use NextGen sequencing, biochemical approaches, mitochondrial assays, and preclinical rodent models of different strains, sexes, and ages to address the following aims. Aim 1: Characterize mtDNA alterations and consequences to OXPHOS function after exposure to a panel of antiviral ribonucleoside analogues. Aim 2: Determine if antiviral ribonucleoside analogues differentially affect mitochondrial function in aged physiology. Even though vaccines are now available for COVID-19, vaccine hesitancy and the appearance of more transmissible SARS-CoV-2 strains are an emerging threat. Also, antiviral nucleoside analogues are often recycled for new viral infections as in the case of Remdesivir which was initially developed against Hepatitis C. This means that these medications may be reused in future viral infections. The research and medical community needs to know whether these antiviral ribonucleoside analogues have off- target side effects, so physicians will be able to make better informed decisions on the costs and benefits of these type of medications for their patients.

项目摘要抗病毒核苷类似物是一种用于防止病毒复制的广谱药物。只 FDA批准的一种COVID-19治疗药物是核苷类似物，并在FDA紧急情况下使用该指令旨在减少治疗感染SARS-CoV-2患者的住院时间。然而，在过去， FDA批准用于控制美国艾滋病毒/艾滋病流行期间感染的抗病毒核糖核苷类似物多年后被证明会导致线粒体DNA突变、线粒体功能障碍、肌病，对治疗的病人造成慢性副作用。该提案涉及这些新的抗病毒药物是否核糖核苷类似物（Remdesivir）是目前FDA批准的唯一一种药物， COVID-19的II/III期临床试验影响线粒体DNA和线粒体功能，导致细胞和组织功能障碍该提案将使用NextGen测序，生物化学方法，线粒体分析，以及不同品系、性别和年龄的临床前啮齿动物模型，以实现以下目的。目标1：描述暴露于一组抗病毒药物后mtDNA的改变和对OXPHOS功能的影响核糖核苷类似物。目的2：确定抗病毒核糖核苷类似物是否差异影响线粒体在老年生理学中的作用尽管现在已有针对COVID-19的疫苗，犹豫不决和出现更易传播的SARS-CoV-2病毒株是一个新出现的威胁。此外，抗病毒核苷类似物经常被回收用于新的病毒感染，如Remdesivir，是针对丙型肝炎的这意味着这些药物可以在未来的病毒感染中重复使用。的研究和医学界需要知道这些抗病毒的核糖核苷类似物是否具有关闭，目标的副作用，因此医生将能够作出更好的知情决定的成本和效益，这类药物对患者的影响。