Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants.

Autor: Liu S; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., Daley EJ; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Tran LM; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., Yu Z; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., Reyes M; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Dean T; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Khatri A; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Levine PM; Departments of Chemistry and Biological Sciences, University of Southern California, Los Angeles, California 90089, United States., Balana AT; Departments of Chemistry and Biological Sciences, University of Southern California, Los Angeles, California 90089, United States., Pratt MR; Departments of Chemistry and Biological Sciences, University of Southern California, Los Angeles, California 90089, United States., Jüppner H; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.; Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States., Gellman SH; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States., Gardella TJ; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2024 Mar 13; Vol. 146 (10), pp. 6522-6529. Date of Electronic Publication: 2024 Feb 28.
DOI: 10.1021/jacs.3c09694
Abstrakt: Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo. This peptide may be of interest for the future development of therapeutic agents that ameliorate PTH1R malfunction.
Databáze: MEDLINE