Reversible modulation of circadian time with chronophotopharmacology

• Published in: Nature communications Vol. 12; no. 1; pp. 3164 - 12
• Main Authors: Kolarski, Dušan, Miró-Vinyals, Carla, Sugiyama, Akiko, Srivastava, Ashutosh, Ono, Daisuke, Nagai, Yoshiko, Iida, Mui, Itami, Kenichiro, Tama, Florence, Szymanski, Wiktor, Hirota, Tsuyoshi, Feringa, Ben L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 140/131; 140/58; 38/5; 631/154/155; 631/45/275; 631/92/458/1733; 639/638/92/436; 639/638/92/96; 64/60; Biological clocks; Casein; Casein kinase I; Circadian rhythm; Circadian rhythms; Enzyme inhibitors; Humanities and Social Sciences; Irradiation; Isoforms; Kinases; Modulation; multidisciplinary; Physiology; Radiation; Science; Science (multidisciplinary); Sleep and wakefulness
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23301-x

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 CKIα and CKIδ isoforms, while upon irradiation it becomes more selective towards CKIδ, revealing the higher importance of CKIδ 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.