Mitoquinone/mitoquinol mesylate as oral and safe Postexposure Prophylaxis for Covid-19

项目摘要/摘要 目前用于治疗SARS-CoV-2感染的口服抗病毒药物，如蛋白酶抑制剂，具有以下局限性 门诊抗病毒5天后无抗炎作用和新冠肺炎反弹 治疗。迫切需要针对SARS-CoV-2的新的抗病毒疗法，理想的情况是也限制 导致新冠肺炎发病的炎症反应。活性氧(ROS)损伤 细胞功能并驱动促炎信号和RNA病毒感染的发病机制 冠状病毒。线粒体是能量和ROS(有丝分裂-ROS)的主要来源。Mito-Ros受 抗氧化剂Nrf2途径，介导病毒感染的发病机制和组织损伤。我们向大家展示了 MitoQ是一种线粒体抗氧化剂和Nrf2激动剂，在体外和体内抑制几种 SARS-CoV-2致病变异体(VOC)与相关的炎症反应和细胞凋亡 上皮细胞通过Nrf2途径。鉴于MitoQ是一种安全且即时的饮食补充剂 作为可能的治疗方法，我们还在人体中展示了MitoQ的抗病毒效果。 精心设计的暴露后预防(PEP)MitoQ与未使用MitoQ的开放标签临床试验 (对照组)，以防止在与高危人群接触后发生SARS-CoV-2感染 确诊为SARS-CoV-2感染。MitoQ的耐受性很好。我们假设MitoQ可以减弱SARS- 冠状病毒-2诱导的上皮细胞MITO-ROS和NRF2通路的异常以及最终导致的组织损伤 重症新冠肺炎的发生发展。此应用程序的目标是确定MitoQ是否可以 作为新的口腔安全门诊暴露后预防治疗重症 新冠肺炎。我们提出了第一个概念验证、随机、双盲、安慰剂对照的第二阶段 口服MitoQ对新冠肺炎高危人群的疗效研究，以进一步 建立MitoQ抗SARS-CoV-2感染的安全性和有效性。我们将包括 2个治疗组(MitoQ每天20毫克，安慰剂)，我们的目标是招募总共112名参与者(50名 每组占10%的自然减员)。疗效的主要结果将是SARS的发展-- 高危暴露后发生CoV-2感染。安全性的主要结果将是参与者的比例 表现出任何等级的不良影响的。鉴于传播的有害主机响应的衰减 病毒复制可能会对产生抗药性病毒施加更高的障碍，这项研究将直接测试MitoQ 作为新冠肺炎对抗新出现的SARS-CoV-2 VOCs的一种新的口服、安全、有效的治疗策略。我们的 该提案将为更大规模的临床试验奠定基础，该试验将推动MitoQ在新冠肺炎中的使用 补充现有的治疗方法。

PROJECT SUMMARY/ABSTRACT Current oral antivirals used against SARS-CoV-2 infection such as protease inhibitors have limitations such as absence of anti-inflammatory effects and rebound COVID-19 after a 5-day course of outpatient antiviral treatment. Novel antiviral therapies against SARS-CoV-2 are urgently needed that ideally also limit inflammatory responses that contribute to morbidity from COVID-19. Reactive oxygen species (ROS) impair cellular functions and drive pro-inflammatory signaling and pathogenesis of infections with RNA viruses like coronavirus. Mitochondria are the main source of energy and ROS (mito-ROS). Mito-ROS are regulated by the antioxidant Nrf2 pathway that mediates pathogenesis and tissue damage of viral infections. We showed that MitoQ, a mitochondrial antioxidant and Nrf2 agonist, inhibits in vitro and in vivo viral replication of several SARS-CoV-2 variants of concern (VOC) and associated inflammatory response and apoptosis in airway epithelial cells through the Nrf2 pathway. Given that MitoQ is a diet supplement that is safe and immediately available to humans for use as possible therapeutic, we also showed antiviral efficacy of MitoQ in humans in a carefully designed open label clinical trial of post exposure prophylaxis (PEP) of MitoQ, compared to no MitoQ (control group), to prevent development of SARS-CoV-2 infection after high-risk exposure to a person with confirmed SARS-CoV-2 infection. MitoQ was well tolerated. We hypothesize that MitoQ attenuates the SARS- CoV-2-induced aberrant mito-ROS and Nrf2 pathway in epithelial cells and ultimately tissue injury that drives development and progression of severe COVID-19. The goal of this application is to determine if MitoQ can be used as novel oral safe outpatient post-exposure prophylaxis treatment against development of severe COVID-19. We propose the first proof-of concept randomized, double-blind, placebo-controlled Phase II efficacy study (RCT) with oral MitoQ use in adults at high risk for development of COVID-19, to further establish the safety and the efficacy of MitoQ against development of SARS-CoV-2 infection. We will include 2 treatment groups (MitoQ 20 mg daily, placebo) and we aim to recruit a total of 112 participants in total (50 per group accounting for 10% attrition). The primary outcome of efficacy will be the development of SARS- CoV-2 infection after high-risk exposure. The primary outcome of safety will be the proportion of participants exhibiting adverse effects of any grade. Given that attenuation of detrimental host responses that propagate viral replication may impose a higher barrier to generation of resistant viruses, this study will directly test MitoQ as a novel oral, safe, potent therapeutic strategy for COVID-19 against emerging SARS-CoV-2 VOCs. Our proposal will set the foundation of larger clinical trial that will advance use of MitoQ for COVID-19 to supplement existing treatments.