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, email@example.com
Sam Gellman | Eurek Alert!
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences