title: Structure-function relationship studies of PTH(1-11) analogues containing D-amino acids.
abstract: Parathyroid hormone (PTH) is an 84-amino acid peptide hormone. Produced in the parathyroid glands, it acts primarily on bone and kidney to maintain extracellular calcium levels within normal limits. It has been shown that the 1-34 amino acid fragment of PTH is sufficient to bind and activate the PTH type-I receptor. Recent investigations focusing on the interaction of N-terminal fragments of PTH with PTH type-I receptor showed that certain modifications can increase signalling potency in peptides as short as 11 amino acids. To understand the role of the side chains of all the amino acid residues in PTH(1-11), we synthesized all-D PTH, three retro-inverso analogues of the most active modified PTH(1-11), H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH(2), and we substituted every L-AA of the latter with the corresponding D-AA, obtaining a library of PTH(1-11) analogues that were tested as agonists. The library was synthesized by SPPS, employing the Fmoc protocol. The biological tests showed that the activity of the D-Har11 analogue is of the same order of magnitude of that of the most active modified PTH(1-11). This behaviour is paralleled by an increase of the helical content on going from the D-Val(2) to the D-Har(11) analogue. This is in agreement with previous work where a correlation between activity and helical content has been demonstrated. The importance of a positively charged group in the C-terminal position is shown to be independent of the configuration of the C(alpha)-carbon.
authors.affiliation: University of Padua, Dept of Chemical Sciences, Padova, Italy. andrea.caporale@unipd.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Caporale
authors.forename: Barbara
authors.initials: B
authors.lastname: Biondi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Schievano
authors.forename: Angela
authors.initials: A
authors.lastname: Wittelsberger
authors.forename: Stefano
authors.initials: S
authors.lastname: Mammi
authors.forename: Evaristo
authors.initials: E
authors.lastname: Peggion
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002942:Circular Dichroism; D006801:Humans; D008969:Molecular Sequence Data; D010281:Parathyroid Hormone / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D044168:Receptor, Parathyroid Hormone, Type 1; C454802:parathyroid hormone (1-11)