Circadian Rhythms in the light of COVID-19: Formulating optimal time-of-day regimens for antiviral drugs using human 3D models and in silico modelling

根据 COVID-19 的昼夜节律：使用人体 3D 模型和计算机建模制定抗病毒药物的最佳时间治疗方案

• 批准号: BB/W010801/1
• 负责人: Vanja Pekovic-Vaughan
• 金额: $ 43.78万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW010801%2F1
• 关键词: Circadian; Rhythms; light; COVID; 19

A number of antiviral, immunomodulatory and anti-inflammatory drugs are being repurposed for COVID-19. Clinical trials worldwide are testing their use as a treatment and/or prophylactic. At present, no clinically available antiviral drugs have been established for SARS-CoV-2. We have recently prioritized promising drug candidates for COVID-19 based on in vivo pharmacokinetic drug modelling in target tissues. Moreover, a number of new animal models are being tested in SARS CoV-2 infections studies in combination with promising drug candidates. Human immune defence, inflammatory responses as well as efficacy of therapeutics and vaccines follow robust daily circadian rhythms, but their role in SARS-CoV-2 infection has yet to be studied. Moreover, recent systems-level studies have defined many host factors and physiological pathways as potential therapeutic targets, many of them which are under the circadian control. To devise therapeutic strategies to counteract SARS CoV-2 infection and the associated COVID-19 pathology, it is crucial to understand how SARS COV-2 affects the host circadian rhythms during infection, and to apply this knowledge towards improved repurposing of existing drugs and development of new drugs and drug formulations. Our interdisciplinary study aims to determine optimal time-of-day regimens for currently repurposed antiviral COVID-19 drugs and develop in silico mathematical models for their time-of-day use in vivo. This will provide time-of-day information on when such drugs exert most potent effects (on viral load and/or viral-induced inflammation) without perturbing circadian clock timing (least toxic). Disruption of circadian timing has serious consequences on many physiological processes especially given its essential role in drug metabolism and recovery from bacterial/viral infections with emerging relevance to SARS-CoV-2. This inter-disciplinary project will lead to novel understanding of how SARS-2 viral infection impacts human circadian rhythms and clock-controlled inflammatory pathways. This project will utilise cutting-edge molecular and biochemical techniques (gene/protein expression, 'omic' profiling, real-time bioluminescence imaging) to analyse cellular and organ-level circadian rhythms upon SARS CoV-2 infection using susceptible human cell types and experimental animal models as well as combined in vitro/in vivo pharmacokinetic drug modelling to project optimal times-of-administration of antiviral drugs in a human setting. This new knowledge will provide new insights on time-of-day dosing profiles of current repurposed COVID-19 drugs, which will have help guide ongoing/future clinical trials to obtain improved clinical outcomes and in vivo experimental studies. This study will also uncover novel drug targets at the interface between circadian control and SARS CoV-2 viral infection to aid development of improved drug formulations thus moving towards precision medicine based on chronotherapy for COVID-19.

许多抗病毒、免疫调节和抗炎药物正在被重新用于COVID-19。世界各地的临床试验正在测试它们作为治疗和/或预防的用途。目前，尚未建立针对SARS-CoV-2的临床可用抗病毒药物。我们最近根据靶组织的体内药代动力学药物模型，优先考虑有前景的COVID-19候选药物。此外，在SARS CoV-2感染研究中，一些新的动物模型正在与有前途的候选药物相结合进行测试。人类免疫防御、炎症反应以及治疗和疫苗的功效遵循强大的每日昼夜节律，但它们在SARS-CoV-2感染中的作用尚未研究。此外，最近的系统水平的研究已经确定了许多宿主因素和生理途径作为潜在的治疗靶点，其中许多是在昼夜节律控制下。为了设计治疗策略来对抗SARS CoV-2感染和相关的COVID-19病理，了解SARS COV-2如何影响感染期间的宿主昼夜节律，并将这些知识应用于改进现有药物的再利用以及新药和药物制剂的开发至关重要。我们的跨学科研究旨在确定目前重新利用的抗病毒COVID-19药物的最佳时间方案，并为其体内使用时间开发计算机数学模型。这将提供关于这些药物何时发挥最有效作用（对病毒载量和/或病毒诱导的炎症）而不干扰生物钟定时（毒性最小）的时间信息。昼夜节律定时的破坏对许多生理过程具有严重后果，特别是考虑到其在药物代谢和从与SARS-CoV-2相关的细菌/病毒感染中恢复的重要作用。这个跨学科的项目将导致对SARS-2病毒感染如何影响人类昼夜节律和时钟控制的炎症通路的新的理解。该项目将利用尖端的分子和生物化学技术（基因/蛋白质表达，“组学”分析，实时生物发光成像），利用易感的人类细胞类型和实验动物模型，以及结合体外/体内药代动力学药物模型，分析SARS CoV-2感染后细胞和器官水平的昼夜节律，以预测抗病毒药物在人类环境中的最佳给药时间。这一新知识将为当前重新利用的COVID-19药物的日剂量分布提供新的见解，这将有助于指导正在进行的/未来的临床试验，以获得改善的临床结果和体内实验研究。这项研究还将在昼夜节律控制和SARS CoV-2病毒感染之间的界面上发现新的药物靶点，以帮助开发改进的药物制剂，从而朝着基于COVID-19时间疗法的精准医学发展。

项目成果

NRF2/KEAP1 pathway is required to fine-tune circadian oscillations as part of the negative feedback loop of the molecular clock: implications for tissue homeostasis and therapeutic interventions

NRF2/KEAP1 通路需要微调昼夜节律振荡，作为分子钟负反馈回路的一部分：对组织稳态和治疗干预的影响

• DOI: 10.1016/j.freeradbiomed.2021.08.042
• 发表时间: 2021
• 期刊: Free Radical Biology and Medicine
• 影响因子: 7.4
• 作者: Sutton E

Antioxidant transcription factor NRF2 regulates skeletal muscle homeostasis through a circadian mechanism that is disrupted with ageing

抗氧化转录因子 NRF2 通过随衰老而扰乱的昼夜节律机制调节骨骼肌稳态

• DOI: 10.1016/j.freeradbiomed.2023.03.042
• 发表时间: 2023
• 期刊: Free Radical Biology and Medicine
• 影响因子: 7.4
• 作者: Pekovic-Vaughan V

The discrepancy between morphological and functional activation of brown adipose tissue in the absence of functional Nrf2

在缺乏功能性 Nrf2 的情况下，棕色脂肪组织的形态和功能激活之间的差异

• DOI: 10.1016/j.freeradbiomed.2023.03.109
• 发表时间: 2023
• 期刊: Free Radical Biology and Medicine
• 影响因子: 7.4
• 作者: Zakic T

A novel role for an antioxidant transcription factor Nrf2 as a transcriptional repressor of the circadian molecular clock

抗氧化转录因子 Nrf2 作为昼夜节律分子钟转录抑制因子的新作用

• DOI: 10.1016/j.freeradbiomed.2021.08.103
• 发表时间: 2021
• 期刊: Free Radical Biology and Medicine
• 影响因子: 7.4
• 作者: Sutton E

Structural and redox-metabolic remodelling of brown adipose tissue in mice lacking nuclear factor erythroid 2-related factor 2 under basal conditions and cold acclimation

基础条件和冷驯化下缺乏核因子红细胞2相关因子2的小鼠棕色脂肪组织的结构和氧化还原代谢重塑

• DOI: 10.1016/j.freeradbiomed.2022.06.035
• 发表时间: 2022
• 期刊: Free Radical Biology and Medicine
• 影响因子: 7.4
• 作者: Zakic T