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

一些抗病毒、免疫调节和抗炎的药物正在被重新用于新冠肺炎。世界各地的临床试验正在测试它们作为治疗和/或预防药物的用途。目前，还没有针对SARS-CoV-2的临床可用的抗病毒药物。我们最近基于靶组织的体内药物动力学模型对新冠肺炎有前景的候选药物进行了优先排序。此外，一些新的动物模型正在SARS CoV-2感染研究中与有希望的候选药物相结合进行测试。人类的免疫防御、炎症反应以及治疗和疫苗的有效性遵循强大的日常昼夜节律，但它们在SARS-CoV-2感染中的作用尚未得到研究。此外，最近的系统水平的研究已经将许多宿主因素和生理途径定义为潜在的治疗靶点，其中许多处于昼夜节律的控制之下。为了制定治疗策略来对抗SARS CoV-2感染和相关的新冠肺炎病理，了解SARS CoV-2在感染期间如何影响宿主的昼夜节律，并将这一知识应用于改进现有药物的再利用和新药和药物配方的开发，是至关重要的。我们的跨学科研究旨在为目前重新调整用途的抗病毒新冠肺炎药物确定最佳的每日时间方案，并建立它们在体内的每日时间使用的电子数学模型。这将提供一天中的时间信息，说明这些药物何时发挥最有效的作用(对病毒载量和/或病毒引起的炎症)，而不会扰乱生物钟的时间(毒性最小)。昼夜节律的紊乱会对许多生理过程造成严重后果，特别是考虑到它在药物代谢和从细菌/病毒感染中恢复所起的重要作用，这与SARS-CoV-2有关。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途径的新理解。该项目将利用尖端分子和生化技术(基因/蛋白质表达、基因组图谱、实时生物发光成像)，使用敏感的人类细胞类型和实验动物模型，分析SARS CoV-2感染后细胞和器官水平的昼夜节律，并结合体外/体内药代动力学药物模型，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调整用途的新冠肺炎药物的每日时间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，以获得更好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病毒感染之间发现新的药物靶点，以帮助改进药物配方的开发，从而走向基于新冠肺炎计时疗法的精准医学。

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.