Reversible modulation of circadian time with chronophotopharmacology

Dušan Kolarski, Carla Miró-Vinyals, Akiko Sugiyama, Ashutosh Srivastava, Daisuke Ono, Yoshiko Nagai, Mui Iida, Kenichiro Itami, Florence Tama, Wiktor Szymanski*, Tsuyoshi Hirota, Ben L. Feringa

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
5 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article number3164
Number of pages12
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - Dec-2021

Cite this