Receptor selectivity from minimal backbone modification of a polypeptide agonist.

ABSTRACT: Human parathyroid hormone (PTH) and N-terminal fragments thereof activate two receptors, hPTHR1 and hPTHR2, which share ∼51% sequence similarity. A peptide comprising the first 34 residues of PTH is fully active at both receptors and is used to treat osteoporosis. We have used this system to explore the hypothesis that backbone modification of a promiscuous peptidic agonist can provide novel receptor-selective agonists. We tested this hypothesis by preparing a set of variants of PTH(1-34)-NH₂ that contained a single β-amino-acid residue replacement at each of the first eight positions. These homologs, each containing one additional backbone methylene unit relative to PTH(1-34)-NH₂ itself, displayed a wide range of potencies in cell-based assays for PTHR1 or PTHR2 acti

SUBMITTER: Liu S 

PROVIDER: S-EPMC6298075 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature