Optimization of PTH/PTHrP Hybrid Peptides to Derive a Long-Acting PTH Analog (LA-PTH).

ABSTRACT: Prolonged signaling at the parathyroid hormone receptor 1 (PTHR1) correlates with the capacity of a ligand to bind to a G protein-independent receptor conformation (R⁰). As long-acting PTH (LA-PTH) ligands hold interest as potential treatments for hypoparathyroidism (HP), we explored the structural basis in the ligand for stable R⁰ binding and prolonged cAMP signaling. A series of PTH/PTHrP hybrid analogs were synthesized and tested for actions in vitro and in vivo. Of the series, [Ala^1,3,12,Gln¹⁰,Arg¹¹,Trp¹⁴]-PTH(1-14)/PTHrP(15-36) (M-PTH/PTHrP) bound with high affinity to R⁰, induced prolonged cAMP responses in UMR106 rat osteoblast-derived cells, and induced the most prolonged increases in serum calcium (sCa) i

SUBMITTER: Noda H 

PROVIDER: S-EPMC7340446 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature