Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Chemical strategy hints at better drugs for osteoporosis, diabetes

17.06.2014

By swapping replacement parts into the backbone of a synthetic hormone, UW–Madison graduate student Ross Cheloha and his mentor, Sam Gellman, along with collaborators at Harvard Medical School, have built a version of a parathyroid hormone that resists degradation in laboratory mice. As a result, the altered hormone can stay around longer — and at much higher concentration, says Gellman, professor of chemistry at the UW.

Hormones are signaling molecules that are distributed throughout the body, usually in the blood. Hormones elicit responses from only those cells that carry appropriate receptor molecules. "Receptors have evolved to recognize a very specific signal in a sea of biological fluids that is full of molecular messages," Gellman says.

The relationship between a receptor and its signaling molecule is often likened to that between a lock and a key.

"We're excited because we have preserved the ability to activate the receptor" by altering the backbone of the hormone, which holds the essential contact points in place, Gellman says. "While retaining, even enhancing, the signaling ability, we have diminished the peptide's susceptibility to the biodegradation mechanisms that nature uses to eliminate signals over time."

Peptides are segments of proteins. Peptide hormones, like the better-known steroid hormones such as estrogen and testosterone, can convey a signal to billions of cells at once, even at tiny concentrations.

For a study published June 15 in Nature Biotechnology, the researchers altered a highly successful synthetic parathyroid hormone called teriparatide, which is used to combat severe osteoporosis.

But the real excitement of the discovery is the potential impact on a large class of peptide drugs, Gellman says. "A substantial group of receptors, including some involved in diabetes, respond to peptide signals, but peptides are quickly degraded in the body. Our approach seems to suggest a general strategy to retain the ability to target a specific receptor while diminishing the action of degrading enzymes. The key is that the receptor is looking for one shape while the destructive enzyme seeks a different shape."

Gellman says the idea of replacing segments of the peptide backbone with artificial units once seemed heretical. "Most people expected that you could not change the backbone, which alters the spacing and orientation of the essential contact points, without making the molecule unrecognizable to the receptor."

Gellman has assigned his rights for the discovery to the Wisconsin Alumni Research Foundation. The study's first author, Cheloha, is a Ph.D. candidate in chemistry at UW-Madison. Co-author Thomas J. Gardella led a team at Harvard Medical School that conducted the biological assessments.

Potentially, the "alter-the-backbone" strategy could allow oral dosing of the rather fragile peptide drugs, which today must be injected to avoid destruction in the stomach and small intestine. By protecting the drugs from degrading enzymes, the new approach could also help sustain higher drug concentrations in the bloodstream.

The altered backbone also seems to make minor changes in signals that the receptor, once activated, transmits into the cell, Gellman says. "Changing the sites of backbone modification results in different profiles of response. Building drug molecules that activate only a certain type of response might allow us to dial out undesired side effects; but that's just a hope at this point."

To date, much of the focus on drug development has concerned the external features of signaling molecules, which directly contact a receptor, Gellman says. "The traditional approach is to keep the skeleton the same and modify the surface components. Our approach is just the opposite, keep the surface components the same, and modify the skeleton. Now that it is clear that this non-traditional approach can be successful, others are likely to try it."

###

The research was funded by National Institutes of Health grant #GM056414 and other sources.

—David Tenenbaum, 608-265-8549, djtenenb@wisc.edu

Sam Gellman | Eurek Alert!
Further information:
http://www.wisc.edu

Further reports about: concentrations drugs enzymes hormones osteoporosis receptor signals skeleton

More articles from Life Sciences:

nachricht A new potential biomarker for cancer imaging
05.02.2016 | Universiti Putra Malaysia (UPM)

nachricht NIH researchers identify striking genomic signature shared by 5 types of cancer
05.02.2016 | NIH/National Human Genome Research Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Automated driving: Steering without limits

OmniSteer project to increase automobiles’ urban maneuverability begins with a € 3.4 million budget

Automobiles increase the mobility of their users. However, their maneuverability is pushed to the limit by cramped inner city conditions. Those who need to...

Im Focus: Microscopy: Nine at one blow

Advance in biomedical imaging: The University of Würzburg's Biocenter has enhanced fluorescence microscopy to label and visualise up to nine different cell structures simultaneously.

Fluorescence microscopy allows researchers to visualise biomolecules in cells. They label the molecules using fluorescent probes, excite them with light and...

Im Focus: NASA's ICESat-2 equipped with unique 3-D manufactured part

NASA's follow-on to the successful ICESat mission will employ a never-before-flown technique for determining the topography of ice sheets and the thickness of sea ice, but that won't be the only first for this mission.

Slated for launch in 2018, NASA's Ice, Cloud and land Elevation Satellite-2 (ICESat-2) also will carry a 3-D printed part made of polyetherketoneketone (PEKK),...

Im Focus: Sinking islands: Does the rise of sea level endanger the Takuu Atoll in the Pacific?

In the last decades, sea level has been rising continuously – about 3.3 mm per year. For reef islands such as the Maldives or the Marshall Islands a sinister picture is being painted evoking the demise of the island states and their cultures. Are the effects of sea-level rise already noticeable on reef islands? Scientists from the ZMT have now answered this question for the Takuu Atoll, a group of Pacific islands, located northeast of Papua New Guinea.

In the last decades, sea level has been rising continuously – about 3.3 mm per year. For reef islands such as the Maldives or the Marshall Islands a sinister...

Im Focus: Energy-saving minicomputers for the ‘Internet of Things’

The ‘Internet of Things’ is growing rapidly. Mobile phones, washing machines and the milk bottle in the fridge: the idea is that minicomputers connected to these will be able to process information, receive and send data. This requires electrical power. Transistors that are capable of switching information with a single electron use far less power than field effect transistors that are commonly used in computers. However, these innovative electronic switches do not yet work at room temperature. Scientists working on the new EU research project ‘Ions4Set’ intend to change this. The program will be launched on February 1. It is coordinated by the Helmholtz-Zentrum Dresden-Rossendorf (HZDR).

“Billions of tiny computers will in future communicate with each other via the Internet or locally. Yet power consumption currently remains a great obstacle”,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

AKL’16: Experience Laser Technology Live in Europe´s Largest Laser Application Center!

02.02.2016 | Event News

From intelligent knee braces to anti-theft backpacks

26.01.2016 | Event News

DATE 2016 Highlighting Automotive and Secure Systems

26.01.2016 | Event News

 
Latest News

A new potential biomarker for cancer imaging

05.02.2016 | Life Sciences

Graphene is strong, but is it tough?

05.02.2016 | Materials Sciences

Tiniest Particles Shrink Before Exploding When Hit With SLAC's X-ray Laser

05.02.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>