posted on 2024-02-28, 20:13authored byShi Liu, Eileen J. Daley, Lauren My-Linh Tran, Zhen Yu, Monica Reyes, Thomas Dean, Ashok Khatri, Paul M. Levine, Aaron T. Balana, Matthew R. Pratt, Harald Jüppner, Samuel H. Gellman, Thomas J. Gardella
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.