Cyclization by a specific lactam increases the ability of human parathyroid hormone (hPTH)-(1-31)NH2 to stimulate bone growth in ovariectomized rats.
Human parathyroid hormone (hPTH)-(1-31)NH2 (Ostabolin), which only stimulates adenylyl cyclase (AC) instead of AC and phospholipase-C as do hPTH(1-84) and hPTH(1-34), strongly stimulates femoral cortical and trabecular bone growth in ovariectomized (OVX) rats. Two side-chain lactams have been introduced in the hydrophilic face of the receptor-binding region of the fragment's Ser17-Val31 amphiphilic alpha-helix in an attempt to develop improved analogs for the treatment of osteoporosis. Replacing the polar Lys27 with an apolar Leu on the hydrophobic face of this alpha-helix and stabilizing the helix with a lactam between Glu22 and Lys26 produced a fragment, [Leu27]-cyclo(Glu22-Lys26)-hPTH(1-31)NH2, which had six times the AC-stimulating ability of hPTH(1-31)NH2 in ROS 17/2 rat osteosarcoma cells, but the other helix-stabilizing lactam derivative [Leu27]-cyclo(Lys26-Arg30)-hPTH(1-31)NH2 did not have a greater AC-stimulating ability than hPTH(1-31)NH2, to stimulate AC in ROS 17/2 rat osteosarcoma cells. As expected from AC stimulation being responsible for PTH's anabolic action, [Leu27]-cyclo(Glu22-Lys26)-hPTH(1-31)NH2 was, depending on the experimental design, a 1.4 to 2 times better stimulator of trabecular bone growth in the OVX rat model than either hPTH(1-31)NH2 or [Leu27]-cyclo(Lys26-Arg30)-hPTH(1-31)NH2. Thus, there is now a more potently anabolic derivative of hPTH(1-31)NH2, [Leu27]-cyclo(Glu22-Lys26)-hPTH(1-31)NH2, which might ultimately prove to be one of the more effective therapeutics for osteoporosis.
Whitfield
J F
JF
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada.
Morley
P
P
Willick
G
G
Langille
R
R
Ross
V
V
MacLean
S
S
Barbier
J R
JR
D000262:Adenylyl Cyclases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D001859:Bone Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007769:Lactams / Q000737:chemistry*; D008970:Molecular Weight; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000517:prevention & control; D012516:Osteosarcoma / Q000473:pathology; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012694:Serine / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014633:Valine / Q000378:metabolism
D007769:Lactams; D010281:Parathyroid Hormone; D010446:Peptide Fragments; C102836:parathyroid hormone (1-31)amide, human; D012694:Serine; D000262:Adenylyl Cyclases; D014633:Valine