Navigation Links
Scripps Research scientists identify first synthetic activator of 2 critical proteins

JUPITER, FL, November 19, 2010 Scientists from the Florida campus of The Scripps Research Institute have identified a novel synthetic activator of a pair of proteins that belong to a protein family playing key roles in human metabolism and immune function. The discovery could provide new and potentially more effective therapeutic approaches to diseases ranging from diabetes to osteoporosis.

The study was published in the November issue (Volume 5, Issue 11) of the journal ACS Chemical Biology.

"This new compound is particularly important because it works in vivo, and it is selective for certain receptors," said Tom Burris, a professor in the Department of Molecular Therapeutics at Scripps Florida who led the study. "These two properties give it significant potential as a possible therapeutic compound."

The new discovery represents the very first synthetic ligand (binding partner) that functions as an agonist (activator) of retinoid-related orphan (ROR) nuclear receptor. Nuclear receptors are protein molecules that mediate hormone activity inside the cell; they have been implicated in the progress of a number of cancers, and have also become drug development targets for diseases including type 2 diabetes, atherosclerosis, and metabolic syndrome.

Although scientists don't know the full therapeutic significance of the new synthetic ligand, its potential usefulness is clear, Burris noted.

"For example, loss of RORα in animal models renders them resistant to weight gain," he said, "while RORγ has been shown to be involved in development of cells that are implicated in autoimmune diseases and loss of RORγ results in animals that are resistant to these types of disease."

RORα has also been shown to be required for normal bone development; animal models lacking this receptor develop osteoporosis, strongly suggesting that RORα agonists may have potential as a treatment of this disease. Osteoporosis affects as many as 44 million Americans, according to the National Institutes of Health. Burris and his colleagues also discovered a pathway stimulating liver secretion of FGF21which has been shown to treat diabetic animalsvia activation of ROR. Diabetes is estimated to affect 23.6 million Americans, according to the National Institutes of Health.

Second Major Discovery

This new agonist is the second that Burris and his Scripps Florida colleagues have identified.

In 2009, Burris and Patrick R. Griffin, chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida, identified a high affinity synthetic inverse agonist of this same pair of nuclear receptors. An inverse agonist, which binds to the same site as an agonist, induces the opposite action of an agonist of that receptor.

For this new study, Burris said they used that first discovery, a compound known as T1317, as a molecular scaffold to synthesize an array of compounds and assess their activity against a number of receptors, including RORα and RORγ.

The one compound that stood out was SR1078, which displayed a unique pharmacological profile that indicated it had a high potential for use as a chemical probe for assessing ROR receptor function in general.

"Unexpectedly, we found that SR1078 functioned as a ROR agonist," Burris said. "When we treated cells with SR1078 we got a significant increase in RORα transcription. Similarly, with RORγ, SR1078 treatment resulted in a stimulation of RORγ dependent transcription activity. Basically, it produced more of these receptor proteins, significantly so."


Contact: Mika Ono
Scripps Research Institute

Related medicine news :

1. Scripps Health Begins Pioneering Study of Human Tumor Sequencing in Cancer Patients
2. Top Scientists Explore the Origin of Life in Annual Lasker Lecture at Scripps Research Institute Florida Campus
3. Scripps Blood & Marrow Transplant Program Celebrates 30th Anniversary of Providing Life-Saving Care
4. Scripps Memorial Hospital La Jolla First in San Diego to Achieve Magnet Nursing Re-designation
5. Scripps Announces Plans for Region's First Proton Therapy Center; $185 Million Facility to Offer Advanced Care to Cancer Patients
6. Scripps Research scientists share $2 million in Florida state research grants
7. Scripps Center for Executive Health Now Offers Genetic Testing
8. Scripps Research scientists uncover previously unknown natural mechanism that controls cocaine use
9. NIH awards Scripps Florida scientists $2.3 Million to develop drug addiction treatments
10. Scripps Research scientists solve long-standing mystery of protein quality control mechanism
11. Scripps and Trius team up to develop new antibiotics with US Department of Defense grant
Post Your Comments:
(Date:11/27/2015)... ... November 27, 2015 , ... According to an article ... American Dental Association meeting in Washington D.C. revolved around the fact that proper dental ... health. The talk stressed the link between periodontal disease (more commonly referred to as ...
(Date:11/27/2015)... , ... November 27, 2015 , ... ... safe and convenient way to dispense prescription medications at home, so he invented ... way to monitor and dispense prescription medications. In doing so, it could help ...
(Date:11/27/2015)... ... November 27, 2015 , ... MPWH, the No.1 Herpes-only dating community in the world, revealed ... 1-1 ). More than 3.7 billion people under the age of 50 – or ... to WHO's first global estimates of HSV-1 infection . , "The data shocks us ...
(Date:11/27/2015)... ... November 27, 2015 , ... ... innovative online platform for mental health and wellness consultation, has collaborated with a ... will bridge the knowledge gap experienced by parents and bring advice from parenting ...
(Date:11/27/2015)... ... 2015 , ... Indosoft Inc., developer and distributor of the ... LTS (Long Term Support) into its Q-Suite 5.10 product line. , Making the ... a version of Asterisk that will receive not only security fixes, but feature ...
Breaking Medicine News(10 mins):
(Date:11/29/2015)... 2015  The GE Health Cloud 1 was unveiled ... North America (RSNA) meeting in ... the new cloud ecosystem and its applications will connect radiologists ... and multidisciplinary teams – both inside and outside the hospital ... of GE. "As the digital industrial leader, we are betting ...
(Date:11/29/2015)... 29, 2015   National Decision Support Company (NDSC) ... base, including notable statewide implementations. As a result, ... ACR Select, more than 1 million times per ... ACR Select provides real-time feedback on the most ... has been implemented at over 100 healthcare systems ...
(Date:11/27/2015)... 27, 2015 --> ... go online. The potential to save costs, improve treatment ... far from fully exploited as yet. Here, particular emphasis ... either via mobile tablet or directly at the patients, ... ) -->      (Photo: ...
Breaking Medicine Technology: