Abstract
Even the most sophisticated watches are imperfect timekeepers and their ability to measure time is affected throughout their lifespan. This problem can be solved by mechanical adjustment or a battery replacement.
The circadian clocks, biological timekeepers that are present in almost every cell of our body, are far more complex systems and generally susceptible to disruption. However, they cannot be repaired. In addition to complexity, the uniform mechanism throughout the cells of the entire organism makes selective time adjustment of a specific disrupted cellular clock almost impossible.
In this study, we present a solution to this problem by judicious incorporation of photoremovable protecting groups (PPGs) and photoswitches into the structure of a known kinase or cryptochrome (CRY) inhibitors that act as circadian clock modulators. Without the incorporation of the photo-responsive groups, these inhibitors cause circadian period lengthening and their effect is not cell-, tissue- or organ-specific. However, the incorporation of photo-responsive groups, enables high temporal and potentially spatial control over inhibitors` activity because light can be delivered with high precision in the human body and the duration of exposure to light can be easily controlled.
Using light and photo-responsive modulators, for the first time we were able to control biological time with high temporal precision. A protected modulator allowed for accurate time dosing in cells, tissue and living organism (zebrafish), while photoswitchable modulators enabled reversible increase and decrease of biological time in cells. With these molecules, a new field of chronophotopharmacology paves the way towards the first chronotherapeutics.
The circadian clocks, biological timekeepers that are present in almost every cell of our body, are far more complex systems and generally susceptible to disruption. However, they cannot be repaired. In addition to complexity, the uniform mechanism throughout the cells of the entire organism makes selective time adjustment of a specific disrupted cellular clock almost impossible.
In this study, we present a solution to this problem by judicious incorporation of photoremovable protecting groups (PPGs) and photoswitches into the structure of a known kinase or cryptochrome (CRY) inhibitors that act as circadian clock modulators. Without the incorporation of the photo-responsive groups, these inhibitors cause circadian period lengthening and their effect is not cell-, tissue- or organ-specific. However, the incorporation of photo-responsive groups, enables high temporal and potentially spatial control over inhibitors` activity because light can be delivered with high precision in the human body and the duration of exposure to light can be easily controlled.
Using light and photo-responsive modulators, for the first time we were able to control biological time with high temporal precision. A protected modulator allowed for accurate time dosing in cells, tissue and living organism (zebrafish), while photoswitchable modulators enabled reversible increase and decrease of biological time in cells. With these molecules, a new field of chronophotopharmacology paves the way towards the first chronotherapeutics.
| Original language | English |
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| Qualification | Doctor of Philosophy |
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| Award date | 8-May-2020 |
| Place of Publication | [Groningen] |
| Publisher | |
| Print ISBNs | 978-94-034-2676-1 |
| Electronic ISBNs | 978-94-034-2677-8 |
| DOIs | |
| Publication status | Published - 2020 |