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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：
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.

项目总结