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

项目总结 抗病毒核苷类似物是一种用于防止病毒复制的广谱药物。仅限 FDA批准的一种新冠肺炎治疗方法是一种核苷类似物，曾在FDA的紧急情况下使用 指示减少住院次数，以治疗感染SARS-CoV-2的患者。然而，在过去， FDA批准用于在美国艾滋病毒/艾滋病流行期间控制感染的抗病毒核糖核苷类似物 几年后被证明会导致线粒体DNA突变，线粒体功能障碍，肌病，以及 对接受治疗的患者造成慢性副作用。这项提案旨在解决这些新型抗病毒药物 核糖核苷类似物(Remdesivir)目前是FDA批准的唯一调节剂或(N4-羟基胞苷) 新冠肺炎II/III期临床试验对线粒体脱氧核糖核酸和线粒体功能的影响 组织功能障碍。这项提案将使用NextGen测序、生化方法、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，以解决以下目标。目标1： 暴露于一组抗病毒药物后线粒体DNA的改变及其对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有不同的影响 线粒体在老年生理学中的作用。尽管现在新冠肺炎上有疫苗可用，但疫苗 犹豫不决和出现更具传播性的SARS-CoV-2毒株是一个新的威胁。还有，抗病毒药物 核苷类似物经常被循环用于新的病毒感染，就像最初被称为Remdesivir的情况一样 这意味着这些药物可能会在未来的病毒感染中重复使用。这个 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- 针对副作用，以便医生能够在更明智的情况下对 这些类型的药物适用于他们的病人。

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.