MEDI 265 |
| PTH mediates its calciotropic activities via PTH1 receptor (PTH1R), a G protein-coupled receptor found in target tissues such as bone and kidney. In vivo, while continuous administration of PTH results in excessive bone resorption, intermittent daily administration of low doses of PTH results in significant bone anabolic effects. Design, synthesis and conformational analysis of PTH(1-34) analogs substituted by beta3-amino acids and alpha,alpha-disubstituted amino acids helped to define the structural nature of the mid-region of this molecule. Extensive photoaffinity crosslinking studies combined with molecular modeling of the PTH-PTH1R system enabled direct mapping of the bimolecular interface leading to an experimentally-based model of the ligand-receptor complex. The non-structured mid-region PTH(1-34) is characterized by enhanced flexibility and was assigned an important functional role in the ligand-receptor interactions. This region anchors the ligand to the juxtamembrane portion of the N-terminal extracellular domain of the PTH1R thus redirecting the N-terminal activation domain of PTH towards the extracellular surface of the heptahelical bundle allowing it to traverses the external surface of the receptor between the tops of the trans-membrane helices 1 and 2 into a position that leads to receptor activation. This integrated approach, which was applied successfully to the PTH--PTH1R system, is currently used to develop small, C-terminal truncated PTH(1-34) peptides and peptidomimetics and may lead to the development of safer, more selective and non-parenterally administered PTH-like bone anabolic drugs. |
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Murray Goodman Memorial Symposium
8:30 AM-12:05 PM, Wednesday, 31 August 2005 Washington DC Convention Center -- Ballroom A, Oral
Division of Medicinal Chemistry |