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VAI Finding Could Lead to Improved Osteoporosis Drug Design

Press Release Number: 
PR-106-VAI-08-1
Date: 
Thursday, July 31, 2008

Drug based on new information could be more potent with fewer side effects

Grand Rapids, MI (July 31, 2008) – Researchers in the Laboratory of Structural Sciences at Van Andel Institute (VAI) have determined how the parathyroid hormone (PTH), which is currently used to treat osteoporosis, precisely binds to its receptor. Drug developers can use this information to aid in the design of more potent therapies for osteoporosis that lack the undesired side effects such as nausea, constipation, muscle weakness, dizziness, leg cramps, and joint pain of current drugs.

“There has been intense interest in designing analogs, or variations, of PTH that lack these side effects,” said Augie Pioszak, Ph.D., a postdoctoral fellow at VAI and lead author of the article that presented the findings in the journal Proceedings of the National Academy of Sciences of the United States of America. “Essential to that goal is a thorough understanding of how the hormone interacts with its receptor, the molecule that translates the signal from the hormone into the biological outcome, in this case bone growth.”

The therapeutic use of PTH was approved by the Food and Drug Administration (FDA) in 2002. A synthetic version of the hormone, marketed in the United States as the drug ForteoTM, is currently used to treat advanced osteoporosis by stimulating new bone formation. The hormone binds to, or fits, its receptor in cells in a very distinct way, much like a key fits a lock.

Using a technique known as X-ray crystallography, the VAI researchers determined the structure of PTH when bound to its receptor at a resolution where individual atoms were observable. This level of detail can help drug developers engineer a drug that more perfectly fits to the receptor, making the drug more potent. The structural information could also help determine if separate elements of the interaction between PTH and its receptor lead to the undesired side effects; then drug developers could manipulate these elements in the drug design to eliminate the side effects.

X-ray crystallography required crystallizing the hormone with its receptor, something that researchers have not been able to accomplish until now. “It is sort of like letting salty water evaporate to form salt crystals,” said Distinguished Scientific Investigator Eric Xu, Ph.D., who heads the VAI lab and is the paper’s co-author. “But the process is much more difficult with hormones and receptors, and researchers have spent years trying to find the ‘magic’ conditions to grow high-quality crystals of PTH with its receptor. We’ve finally found a method that works.”

The method developed by the VAI researchers is applicable to other receptor-hormone pairs similar to PTH and its receptor, such as those that have therapeutic value for the treatment of Type II diabetes. “This could help us optimize drug design for several diseases,” said Xu.

Established by Jay and Betty Van Andel in 1996, Van Andel Institute is an independent research organization dedicated to preserving, enhancing and expanding the frontiers of medical science, and to achieving excellence in education by probing fundamental issues of education and the learning process.

The original news release can be found at: http://www.vai.org/News/News/2008/07_31_XuOsteoporosis.aspx

Note: Published in the Proceedings of the National Academy of Sciences of the United States of America, PNAS April 1, 2008 vol. 105 no. 13 5034-5039; doi: 10.1073/pnas.0801027105; Augen A. Pioszak and H. Eric Xu; "Molecular recognition of parathyroid hormone by its G protein-coupled receptor".

A native diffraction dataset was measured from a single crystal at the Advanced Photon Source (Argonne National Laboratory), beamline 21-ID-D (LS-CAT). Argonne National Laboratory is funded by the U.S. Department of Energy's Office of Science.

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