The change of circadian rhythm: an interview with Dr. Doug Kojetin, The Scripps Research Institute -
Interview by April Cashin-Garbutt , BA Hons (Cantab)
Dr. Douglas Kojetin THOUGHT LEADERS SERIES ... overview of the world's foremost experts please can you give a brief overview of the circadian rhythm?
human circadian rhythm is a "clock" that internal controls many physiological processes in the body.
circadian rhythms are affected by many different stimuli such as sleep and light, which are the most widely appreciated ways, but also eating- of which can modulate or change, important processes in our body such as temperature, the production of hormones or other signaling small molecules, cell regeneration, and others.
How much is currently known about the physiological processes that underlie circadian rhythm in humans?
It became clear that the circadian rhythm is an important physiological control mechanism in our body, not only in terms of regulation of whole organs such as the brain, but studies have also shown that the circadian rhythm persists (and can be controlled to affect) individual cells in our body.
and significant advances, more recently, there has been to identify proteins and receptors that are involved in the regulation of the human circadian rhythm. Some proteins, such as REV-ERB receptors appear to be druggable, indicating that we may be able to design drugs to alter circadian rhythm.
What potential benefits would be the ability to alter the circadian rhythm have?
There are probably many potential benefits of the drug design to modify the circadian rhythm. It is possible these drugs could cure sleep disorders, for example, or extending vigilance in cases where it may be appropriate or necessary to do so.
In addition, the malfunction in the circadian rhythm is involved in many diseases. For example, people who work the night shift have a higher risk for a number of diseases, including addiction, depression, obesity, cardiovascular problems, cancer and problems family / house. Drugs targeting the circadian rhythm can help treat these types of questions and more.
It was recently announced that you had discovered a pair of compounds that could potentially alter the circadian rhythm. What are these compounds and how did you find them?
These are compounds which bind to and affect the function of a class of receptors known as the REV-ERB. These compounds are similar to natural porphyrin ligand present in the body, heme.
Heme, which contains an iron metal center, is the natural ligand for the REV-ERB receptors. We were curious if REV-ERB could bind to a molecule of heme-like with a different metal center that normally found in the body.
In our study published in the Journal of Biological Chemistry , it shows that two similar additional heme porphyrins, which contain cobalt or zinc instead of iron, can bind similar to REV-ERB heme but it is interesting that they have functional effects on activity REV-ERB.
How is REV-ERB normally regulated and why cobalt protoporphyrin IX (COPP) and zinc protoporphyrin IX (ZnPP) have a different effect on REV-ERB?
the natural ligand for REV-ERB in the cell is heme, and it is believed that when heme binds to the REV-ERB activates its ability to function.
Our study has observed that changing the metal center of the scaffolding porphyrin heme called protoporphyrin IX-iron or cobalt (COPP) or zinc (ZnPP) inhibits the function of REV -ERB.
to determine why Copp and ZnPP inhibits the REV-ERB function, we studied how the compounds bind to REV-ERB on the atomic level. Interestingly, or perhaps unfortunately, the results were actually very similar to other published studies on heme linked REV-ERB. This indicates that there are likely more complex functional mechanisms at play here, as opposed to simply compound binding to REV-ERB.
In fact, other studies have shown that the REV-ERB function can be affected by small molecular gas in our body, such as molecular oxygen (O2), carbon monoxide (CO ) and nitric oxide (NO) in the binder / REV-ERB heme complex. Our data indicate that Copp ZnPP and change of the metal center may affect the capacity of these small gas molecules to bind to the REV-ERB.
How you discovered compounds could be used to discover new treatments for diabetes and obesity?
There is a great interest in the "synthetic" design compounds that can alter the circadian rhythm and optimize them for use as therapeutic agents in humans. Unfortunately, many compounds which are synthetically developed by medicinal chemistry approaches can be toxic in the body.
Once nice feature about Copp and ZnPP is that they are derived from a natural product commonly found in the body, heme, which is a natural ligand for the REV-ERB. In fact, previous studies have shown that CoPP has functional effects "in vivo" (in mice), including anti-obesity activity.
What impact do you think your results will be and what the next steps in your research?
In other studies, we designed compounds REV-ERB "synthetic" that alter circadian rhythm. However, all these "synthetic" compounds are agonists Rev-erb (or activators). Thus, these novel compounds, and Copp ZnPP, which are antagonists REV-ERB (inhibitors), can provide a unique tool to determine how the different classes of potential future drugs REV-ERB (vs. activator inhibitors) can alter the pace circadian.
in addition to working with other scientists to determine their functional effects in vivo, we also work to study the molecular details of why change the metal center of the heme natural ligand may cause an opposite effect on the activity REV-ERB.
to what extent do you think that we will be able to alter the circadian rhythm in the future? What are the main limiting factors?
Although we have come a long way in understanding how circadian rhythms are controlled, there is still a lot we do not know. Certainly dysfunctional circadian rhythm can cause the disease, and medication can be a viable treatment, but there are always risks with a drug to treat a disorder.
In addition, the main challenge for all drug development project is the optimization of drugs for use in humans. Although a compound can show beneficial effects in laboratory parameters controlled or in animal models, we can not easily predict whether the same compound can be tolerated in humans and it can take years to work around this bottleneck.
where readers find more information?
Our study was published in the Journal of Biological Chemistry . The text can be found on the website of the journal:
http://www.jbc.org/content/early/2014/05/28/jbc.M113.545111.abstract
and the US national Library of medicine website "PubMed" of
http://www.ncbi.nlm.nih.gov/pubmed/24872411
More information about the Kojetin laboratory work can be found at the following address: http://www.scripps.edu/kojetin/
about Dr. Doug Kojetin
Dr. Kojetin research laboratory focuses on a class called human receptors "nuclear receptor", which are important transcription factors that are the targets of a large number of drugs in clinical use.
Their research is focused on understanding the molecular and atomic details of how natural small molecules, currently available drugs and new synthetic compounds bind to nuclear receptors affect their function. Research in the laboratory Kojetin is currently supported by the National Institutes of Health (NIH).
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