Science Topics – 187
We have discovered a novel compound, “Mic-628,” that specifically induces the expression of the mammalian clock gene Per1. When Mic-628 was administered to mice, both the central (brain) and peripheral circadian clocks advanced simultaneously regardless of the timing of administration. This significantly shortened the recovery period from jet lag from the usual 7 days to just 4 days.Mechanistically, Mic-628 directly binds to the transcriptional repressor CRY1, promoting its interaction with the clock protein complex (CLOCK-BMAL1). We found that this combined complex acts on a genetic switch known as the “double E-box sequence” to specifically turn on Per1 transcription. Furthermore, mathematical modeling revealed that the “auto-inhibitory mechanism” exerted by the newly induced PER1 protein itself is responsible for this stable, time-independent clock-advancing effect. These findings not only deepen our understanding of the fundamental operating principles of the circadian clock but are also expected to lead to the development of innovative therapeutics for circadian rhythm sleep disorders. As a “smart drug,” Mic-628 uniquely and consistently advances the clock regardless of when it is taken.
Title: A Period1 inducer specifically advances circadian clock in mice
Authors: Yoshifumi Takahata, Yuki Kasashima, Takuya Yoshioka, Shusei Yashiki, Justina Kulikauskaite, Tomoaki Matsuura, Yuki Ohba, Hideaki Hasegawa, Naoki Yuri, Nagisa Iwai, Nanako Otsu, Mikiya Kitakata, Yuta Kitaguchi, Haruki Furune, Chihiro Omori, Mutsumi Mukai, Yuki Komamura-Kohno, Yi-Ying Huang, Matsumi Hirose, Nobuya Koike, Yoichi Yamada, Kazuo Nakazawa, Kumiko Ui-Tei, Yoshiyuki Sakaki, Rika Numano, Koichiro Uriu, and Hajime Tei.
Journal: Proceedings of the National Academy of Sciences of the United States of America (PNAS), 123 (e2509943123), 2026.
＜Figure Legends＞
How Mic-628 advances the circadian clock.
When administered to mice, Mic-628 acts on both the “central clock” in the brain and the “peripheral clocks” throughout the body, advancing the onset of their daily activity by approximately 2 hours. At the molecular level, Mic-628 binds to a clock protein (CRY1) and changes its structure. This promotes the action of another protein complex (CLOCK-BMAL1), causing it to bind to a specific genetic switch (double E-box) and strongly turn on the Per1 gene. The newly produced PER1 protein then acts as a brake (feedback inhibition), leading to a stable advancement of the circadian clock.
1 Genome Editing Research and Development Unit, Graduate School of Dentistry, University of Osaka, 2 Graduate School of Natural Science and Technology, Kanazawa University, 3 School of Life Science and Technology, Institute of Science Tokyo, 4 Toyohashi University of Technology