| Abstract
| - Both the parathyroid hormone (PTH) and the functionallysimilar parathyroid hormone-relatedprotein (PTHrP) have served as templates for the development of novelbone anabolic agentsfor the treatment of osteoporosis. The PTHrP analog RS-66271(Vickery, B. H.; Avnur, Z.;Cheng, Y.; Chiou, S.-S.; Leaffer, D.; Caulfield, J. P.; Kimmel, D.B.; Ho, T.; Krstenansky, J.L. J. Bone Miner. Res.1996, 11, 1943−1951), in which theamino acids 22−31 have beensubstituted by the sequenceE22-L-L-E-K-L-L-E-K-L31 (a model amphiphilicpeptide), is a potentbone anabolic agent invivo. Therefore,RS-66271 is a good candidate for structural analysiswith the aim of developing a structure−activity relationship.The structural characterizationdescribed here was carried out in aqueous solution employing circulardichroism and nuclearmagnetic resonance spectroscopy. We find that the incorporatedamphiphilic decapeptide isindeed helical. In addition, it induces the adjacent residues, upto residue 16, to adopt thehelical conformation. The helical domain, including residues16−32, incorporates most of thepreviously identified principal receptor binding domainPTHrP(25−34). We discuss therelevance of the distinct and extensive helicity in light of thereduced invitro receptor affinity/activity and the enhanced invivo bone anabolicefficacy of RS-66271.
|
