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

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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.