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：
10557154
负责人：
Alicia M Pickrell
金额：
$ 19.32万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10557154
关键词：
2019-nCoV 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 Cardiac Cell Culture Techniques Cells Chemicals Chronic Clinical Trials Communities Costs and Benefits DNA DNA Damage Developing Countries Echocardiography Emergency Situation Enzymes Epidemic Evaluation Exposure to FDA approved Functional disorder Future Generations Genetic Transcription HIV/AIDS Health Hepatitis C Histopathology Hospitalization Immunocompromised Host In Situ Individual Infection Infection Control Ionophores Lasers Marketing Mediation Medical Microscopy Mitochondria Mitochondrial DNA Mutagens Mutation Analysis 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 Predisposition 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 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 cardiogenesis combat evaluation/testing exposed human population in vivo infection rate mature animal mitochondrial DNA alteration 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.

项目概要抗病毒核苷类似物是一种用于预防病毒复制的广谱药物。仅有的 FDA 批准的一种治疗 COVID-19 的药物是核苷类似物，并在 FDA 紧急情况下使用指令减少治疗 SARS-CoV-2 感染患者的住院时间。然而，在过去， FDA 批准抗病毒核糖核苷类似物用于在美国艾滋病毒/艾滋病流行期间控制感染数年后被证明会导致线粒体 DNA 突变、线粒体功能障碍、肌病和对接受治疗的患者造成慢性副作用。该提案讨论了这些新型抗病毒药物是否核糖核苷类似物（瑞德西韦）是目前 FDA 批准的唯一药物或（N4-羟基胞苷） 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。该提案将使用下一代测序、生化方法、线粒体测定、以及不同品系、性别和年龄的临床前啮齿动物模型，以实现以下目标。目标 1：表征暴露于一组抗病毒药物后 mtDNA 的改变以及对 OXPHOS 功能的影响核糖核苷类似物。目标 2：确定抗病毒核糖核苷类似物是否有不同影响老年生理学中的线粒体功能。尽管现在已有针对 COVID-19 的疫苗，但疫苗犹豫不决和更具传染性的 SARS-CoV-2 毒株的出现是一个新出现的威胁。还有抗病毒核苷类似物经常被回收用于新的病毒感染，就像瑞德西韦最初被回收的情况一样。针对丙型肝炎而开发的药物。这意味着这些药物可以在未来的病毒感染中重复使用。这研究和医学界需要知道这些抗病毒核糖核苷类似物是否具有副作用针对副作用，因此医生将能够就副作用的成本和收益做出更明智的决定为患者提供这些类型的药物。