Compound with Potent Effects on the Biological Clock Discovered)

In December, 2010,

The researchers discovered longdaysin by screening thousands of compounds with a chemical robot. (Credit: UC San Diego)

A team of researchers from UC San Diego and three other research institutions has discovered a molecule with the most potent effects ever seen on the biological clock.

They used an automated screening technique developed by pharmaceutical companies to find new drugs.

Londaysin For Those Who Need To Reset Biological Clock
28th December, 2010

Have you ever had serious problems with your biological clock when you travel from Europe to the States? Have you ever thought, how do the people who regularly have to travel between the continents, manage their sleep problems? This can be really hard, you know. To help those people, as well as everyone who needs to adjust his biological clock, a group of scientists at the University of California-San Diego in association with three other research organizations developed a new innovative substance which received a name “longdaysin”. It can be effectively used to prologue your biological day for as much as 10 hours.

On the initial stage of the studies, the scientists from Japan leaded by Tsuyoshi Hirota found outlongdaysin compound during their genetic researches. In order to find possible clues to creating a cure for cancer, the scientists experimented with luciferase genes by attaching them to human cancer cells. The scientists noticed that these genes caused changes in circadian rhythms of cells, this way prolonging the period of cell activities. A genetic research robot analyzed more than 120,000 possible compositions of molecular compounds to find out which of them were able to change the circadian rhythms of the cells the most.

Then, the results of these experiments were sent to San Diego University, where American specialists continued lab trials and managed to receive isolated longdaysin. American scientists worked with the samples of larval zebra fish tissues and by changing the concentration of the substance the researchers managed to receive correspondent chronobiological effects on the living cells. Further, the experiments were carried on with various mouse tissues.

Steve Kay, one of the specialists from San Diego university says: “Theoretically, longdaysin or a compound like it could be used to correct sleep disorders such as the genetic disorder familial advanced sleep syndrome, which is characterized by a clock that’s running too fast.” The scientists plant to continue their work and formulate a special medication which will help people stay awake longer is they need that. It can be helpful not only for travelers, but for those people who work shifts. Read more about the findings of this interesting research in the December issue of PLoS Biology.

what do the researchers say?

"Theoretically, longdaysin or a compound like it could be used to correct sleep disorders such as the genetic disorder familial advanced sleep syndrome, which is characterized by a clock that's running too fast," said Steve Kay, dean of UCSD's Division of Biological Sciences, who headed the research team, which published its findings in the December 14 issue of the journal PLoS Biology. "A compound that makes the clock slow down or speed up can also be used to phase-shift the clock -- in other words, to bump or reset the hands of the clock. This would help your body catch up when it is jet lagged or reset it to a normal day-night cycle when it has been thrown out of phase by shift work."

The researchers demonstrated the dramatic effects of longdaysin by lengthening the biological clocks of larval zebra fish by more than 10 hours.

"Longdaysin is the champion by far in how much it can move the clock," said Kay, whose laboratory at UCSD had found compounds in previous studies that could shift the biological clock by as much as several hours at most. "We were really surprised to find out how much you can slow down the biological clock with this compound and still have a clock that is running."

The researchers then showed that longdaysin had the same effect of lengthening the biological clock in mouse tissue samples and zebra fish larvae that carried luciferase genes attached to their clock genes.

"We were really encouraged to find that when we added longdaysin to these living zebra fish, we lengthened the biological clock and didn't see any obvious deleterious effects," said Kay. "They grow normally while they are exposed to this compound. That showed us that our high-throughput assay works and accurately predicts how the compound works on the biological clock of a living fish. The next thing to do is to try this in a mammalian system."

Kay's research team plans to test longdaysin on mice in the near future, but its goal isn't to develop longdaysin into a drug."Longdaysin is not as potent as we would like," he adds.

"This will be a tool for research.

Once Kay's group had isolated longdaysin, it turned to biological chemists in Peter Schultz's laboratory at The Scripps Research Institute to characterize the molecule and figure out the mechanisms of how it lengthened the biological clock. That analysis showed that three separate protein kinases on the compound were responsible for the dramatic effect of longdaysin, one of which, CK1alpha, had previously been ignored by chronobiology researchers.

"Because this compound doesn't just hit one target, but multiple targets, it showed us that if you want to shift the biological clock in a major way you have to hit multiple kinases," said Kay


“Dubbed by the scientists "longdaysin," for its ability to dramatically slow down the biological clock, the new compound and the application of their screening method to the discovery of other clock-shifting chemicals could pave the way for a host of new drugs to treat severe sleep disorders or quickly reset the biological clocks of jet-lagged travelers who regularly travel across multiple time zones”