Reversible modulation of circadian time with chronophotopharmacology

The circadian clock controls daily rhythms of physiological processes. The presence of the clock mechanism throughout the body is hampering its local regulation by small molecules. A photoresponsive clock modulator would enable precise and reversible regulation of circadian rhythms using light as a bio-orthogonal external stimulus. Here we show, through judicious molecular design and state-of-the-art photopharmacological tools, the development of a visible light-responsive inhibitor of casein kinase I (CKI) that controls the period and phase of cellular and tissue circadian rhythms in a reversible manner. The dark isomer of photoswitchable inhibitor 9 exhibits almost identical affinity towards the CKI alpha and CKI delta isoforms, while upon irradiation it becomes more selective towards CKI delta, revealing the higher importance of CKI delta in the period regulation. Our studies enable long-term regulation of CKI activity in cells for multiple days and show the reversible modulation of circadian rhythms with a several hour period and phase change through chronophotopharmacology. The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.

Automated summary

This study presents the development of a visible light-responsive inhibitor of casein kinase I, enabling precise and reversible control of cellular and tissue circadian rhythms. The inhibitor can switch between CKI isoforms and reveal the importance of CKI delta in period regulation, allowing for long-term regulation of CKI activity and reversible modulation of circadian rhythms through chronophotopharmacology.