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 Scientists uncover the role of a protein in production & survival of myelin-forming cells
19.07.2018 | Advanced Science Research Center, GC/CUNY

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Future electronic components to be printed like newspapers

A new manufacturing technique uses a process similar to newspaper printing to form smoother and more flexible metals for making ultrafast electronic devices.

The low-cost process, developed by Purdue University researchers, combines tools already used in industry for manufacturing metals on a large scale, but uses...

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

A smart safe rechargeable zinc ion battery based on sol-gel transition electrolytes

20.07.2018 | Power and Electrical Engineering

Reversing cause and effect is no trouble for quantum computers

20.07.2018 | Information Technology

Princeton-UPenn research team finds physics treasure hidden in a wallpaper pattern

20.07.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>