Analogues of human parathyroid hormone (1-31)NH(2): further evaluation of the effect of conformational constraint on biological activity.
A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys(18)-Asp(22))[Ala(1),Nle(8),Lys(18),Asp(22),Leu(27)]hPTH(1-31)NH(2) (2, EC(50)=0.29nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1-34). Other locations within the primary sequence of hPTH(1-31)NH(2) were evaluated by the placement of the [i, i+4] lactam constraining element. Ring size and lactam orientations at the 18-22 positions were also examined.
Condon
Stephen M
SM
Department of Medicinal Chemistry, Rhône-Poulenc Rorer Research and Development, 500 Arcola Road, Collegeville, PA 19426, USA. scondon@viropharma.com
Darnbrough
Shelley
S
Burns
Christopher J
CJ
Bobko
Mark A
MA
Morize
Isabelle
I
Uhl
Joanne
J
Jariwala
Navinchandra U
NU
Burke
Kathleen
K
Labaudiniere
Richard F
RF
D000262:Adenylyl Cyclases / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D007769:Lactams / Q000737:chemistry; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D051381:Rats; D018016:Receptors, Parathyroid Hormone / Q000819:agonists; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D007769:Lactams; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D018016:Receptors, Parathyroid Hormone; C101312:parathyroid hormone (1-31); D000262:Adenylyl Cyclases