Ligand-dependent effects of methionine-8 oxidation in parathyroid hormone peptide analogs

Thomas Gardella, Vsevolod Katritch, Saheem Zaidi, Eileen Daley, Ashok Khatri & Jean-Pierre Vilardaga
LA-PTH is a long-acting parathyroid hormone (PTH) peptide analog in pre-clinical development for hypoparathyroidism (HP). Like native PTH, LA-PTH contains a methionine at position 8 that is predicted to be critical for function. We assessed the impact of methionine oxidation on the functional properties of LA-PTH and control PTH ligands. Oxidation of PTH(1-34) resulted in marked (~20-fold) reductions in binding affinity on the PTH receptor-1 (PTHR1) in cell membranes, similarly diminished potency for cAMP signaling...
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