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The Nagoya University Institute of Transformative Bio-Molecules (WPI-ITbM) research team of Designated Associate Professor Tsuyoshi Hirota, Postdoctoral Fellow Simon Miller, Professor Kenichiro Itami and grad student Tsuyoshi Oshima (Research Fellowship for Young Scientists, JSPS), in collaboration with the team of Professor Ben Feringa and Postdoctoral Fellow Dušan Kolarski of Groningen University in the Netherlands, have achieved a world first: fully conducive manipulation of the period of the circadian clock with mild, by exchanging part of a compound using a light-activated switch.
Waking in the morning, sleeping at night – the majority of our biological activities repeat within a daily cycle. The internal process which governs this rhythm is called the circadian clock. While it’s understood that the circadian clock is controlled by the joint functions of clock genes and clock proteins, the process by which it can control and stabilize the rhythm over the lengthy period of a day has been shrouded in mystery.
To be able to handle this issue, the researchers found a chemical biology process for large-scale analysis of the effect of compounds on the circadian rhythm in cultured human cells, elucidating the substantial molecular mechanisms that determine the daily interval.
This large-scale chemical screening identified two chemicals – TH303 and its analogue TH129 – that lengthened the circadian clock period. The study team then worked on elucidating how these chemicals interact with the clock protein CRY1 at a molecular level with X-ray crystallography. They found that part of those compounds, called a benzophenone, owned a similar arrangement to the cis isomer of azobenzene, a light-activated switch.
When they then examined the response to light of GO1323, a version of TH129 where benzophenone is displaced by azobenzene, they found that its structure changed to the cis isomer under ultraviolet light, and back to the trans isomer under white light. According to computer simulations, the cis isomer of GO1323 interacts identically to TH129 with CRY1, while the trans isomer doesn’t have any interaction with it.
Thus, when exposed to ultraviolet light, the circadian clock period of cultured human cells which had been treated with GO1323 was extended compared with those that were kept in the dark. What’s more, when exposed to white light, these cells’ circadian clock period returned to normal, demonstrating that the process is reversible. As ultraviolet light is damaging to cells, the research team had to find a way to adapt the process to use a non-harmful area of the spectrum to extend the period. They synthesized GO1423, containing tetraorthofluoroazobenzine.
This compound adjustments to its cis isomer under green light, and to its trans isomer under purple light, while maintaining the other desirable characteristics of GO1323. When cells treated with GO1423 were exposed to green light, their circadian rhythm period was extended compared with those that were kept in the dark, and when exposed to violet light, the result was reversed. Thus, the researchers succeeded in producing a reversible way of controlling the circadian clock period using visible light.
Control of the circadian clock with methods such as these is expected to contribute to the treatment of related diseases such as sleep disorders, metabolic syndrome and cancer, and this research achievement represents an important and exciting step forward in the area.
Institute of Transformative Bio-Molecules (ITbM), Nagoya University
Kolarski, D., et al. (2021) Photopharmacological Manipulation of Mammalian CRY1 for Regulation of the Circadian Clock. Journal of the American Chemical Society. doi.org/10.1021/jacs.0c12280.