A theoretical systems chronopharmacology approach for COVID-19: Modeling circadian regulation of lung infection and potential precision therapies.

The COVID-19 pandemic, caused by SARS-CoV-2, has underscored the urgent need for innovative therapeutic approaches. Recent studies have revealed a complex interplay between the circadian clock and SARS-CoV-2 infection in lung cells, opening new avenues for targeted interventions. This systems pharmacology study investigates this intricate relationship, focusing on the circadian protein BMAL1. BMAL1 plays a dual role in viral dynamics, driving the expression of the viral entry receptor ACE2 while suppressing interferon-stimulated antiviral genes. Its critical position at the host-pathogen interface suggests potential as a therapeutic target, albeit requiring a nuanced approach to avoid disrupting essential circadian regulation. To enable precise tuning of potential interventions, we constructed a computational model integrating the lung cellular clock with viral infection components. We validated this model against literature data to establish a platform for drug administration simulation studies using the REV-ERB agonist SR9009. Our simulations of optimized SR9009 dosing reveal circadian-based strategies that potentially suppress viral infection while minimizing clock disruption. This quantitative framework offers insights into the viral-circadian interface, aiming to guide the development of chronotherapy-based antivirals. More broadly, it underscores the importance of understanding the connections between circadian timing, respiratory viral infections, and therapeutic responses for advancing precision medicine. Such approaches are vital for responding effectively to the rapid spread of coronaviruses like SARS-CoV-2.