Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution
Year: 2017
Type: article
Abstract: The parathyroid hormone receptor 1 (PTHR1) is a member of the B-family of GPCRs; these receptors are activated by long polypeptide hormones and constitute targets of drug development efforts. Parathyroid hormone (PTH, 84 residues) and PTH-related protein (PTHrP, 141 residues) are natural agonists of PTHR1, and an N-terminal fragment of PTH, PTH(1-34), is used clinically to treat osteoporosis. Conventional peptides in the 20-40-mer length range are rapidly degraded by proteases, which may limit their biomedical utility. We have used the PTHR1-ligand system to explore the impact of broadly distributed replacement of α-amino acid residues with β-amino acid residues on susceptibility to proteolysis and agonist activity. This effort led us to identify new PTHR1 agonists that contain α → β replacements throughout their sequences, manifest potent agonist activity in cellular assays, and display remarkable resistance to proteolysis, in cases remaining active after extended exposure to simulated gastric fluid. The strategy we have employed suggests a path toward identifying protease-resistant agonists of other B-family GPCRs.
Source: Journal of Medicinal Chemistry
Authors: Ross W. Cheloha, Bingming Chen, Niyanta N. Kumar, Tomoyuki Watanabe, Robert G. Thorne, Lingjun Li, Thomas J. Gardella, Samuel H. Gellman
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Wisconsin Alumni Research Foundation, National Institutes of Health, Institute for Clinical and Translational Research, University of Wisconsin, Madison, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: Acquisition of a High-Field Dual Source FTICR-MS for Pharmaceutical Research, Novel Agonists and Inverse Agonists for B-Family GPCRs, Hormonal Control of Calcium Metabolism, Biotechnology Training Program, Institutional Clinical and Translational Science Award, CENTER FOR SKELETAL RESEARCH, Institutional Clinical and Translational Science Award
OpenAlex ID: W2765712976