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预防病毒复制的广谱药物。仅有的 FDA批准的COVID-19治疗是一种核苷类似物，在FDA紧急情况下使用减少住院时间以治疗感染SARS-COV-2的患者的指令。但是，过去， FDA批准的抗病毒核糖核苷类似物用于控制美国HIV/AIDS流行期间感染几年后显示的导致线粒体DNA突变，线粒体功能障碍，肌病和对治疗患者造成慢性副作用。该提议解决了这些新颖的抗病毒核糖核苷类似物（Remdesivir）当前是唯一的FDA批准的调解或（N4-羟基霉素） II/III期COVID-19的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。该建议将使用NextGen测序，生化方法，线粒体测定，以及不同菌株，性别和年龄的临床前啮齿动物模型，以解决以下目标。目标1：表征MTDNA的改变以及暴露于抗病毒面板后的Oxphos功能的后果核糖核苷类似物。 AIM 2：确定抗病毒核糖核苷是否差异影响老年生理学的线粒体功能。即使现在可用于19.19的疫苗，疫苗犹豫和更可传播的SARS-COV-2菌株的外观是一种新兴的威胁。另外，抗病毒核苷类似物通常被回收用于新的病毒感染，例如最初是Remdesivir的情况针对丙型肝炎开发。这意味着这些药物可能会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有远处目标副作用，因此医生将能够就成本和收益做出更好的知识决定这些类型的药物为他们的患者。