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

Overview

Journal J Am Chem Soc

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Feb 28

PMID 38417010

Authors

Shi 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 Juppner

Samuel H Gellman

Thomas J Gardella

Affiliations

Soon will be listed here.

Abstract

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.

References

Liu S, Cheloha R, Watanabe T, Gardella T, Gellman S . Receptor selectivity from minimal backbone modification of a polypeptide agonist. Proc Natl Acad Sci U S A. 2018; 115(49):12383-12388. PMC: 6298075. DOI: 10.1073/pnas.1815294115. View

Boyce E, Mai Y, Pham C . Abaloparatide: Review of a Next-Generation Parathyroid Hormone Agonist. Ann Pharmacother. 2017; 52(5):462-472. DOI: 10.1177/1060028017748649. View

Schipani E, Langman C, Hunzelman J, Le Merrer M, Loke K, Dillon M . A novel parathyroid hormone (PTH)/PTH-related peptide receptor mutation in Jansen's metaphyseal chondrodysplasia. J Clin Endocrinol Metab. 1999; 84(9):3052-7. DOI: 10.1210/jcem.84.9.6000. View

Cheloha R, Watanabe T, Dean T, Gellman S, Gardella T . Backbone Modification of a Parathyroid Hormone Receptor-1 Antagonist/Inverse Agonist. ACS Chem Biol. 2016; 11(10):2752-2762. PMC: 5107307. DOI: 10.1021/acschembio.6b00404. View

Schipani E, Langman C, Parfitt A, Jensen G, Kikuchi S, Kooh S . Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N Engl J Med. 1996; 335(10):708-14. DOI: 10.1056/NEJM199609053351004. View

Hattersley G, Dean T, Corbin B, Bahar H, Gardella T . Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology. 2015; 157(1):141-9. PMC: 4701881. DOI: 10.1210/en.2015-1726. View

Liu S, Yu Z, Daley E, Bingman C, Bruchs A, Gardella T . Altered signaling at the PTH receptor via modified agonist contacts with the extracellular domain provides a path to prolonged agonism in vivo. Proc Natl Acad Sci U S A. 2022; 119(48):e2212736119. PMC: 9860328. DOI: 10.1073/pnas.2212736119. View

Outlaw V, Cheloha R, Jurgens E, Bovier F, Zhu Y, Kreitler D . Engineering Protease-Resistant Peptides to Inhibit Human Parainfluenza Viral Respiratory Infection. J Am Chem Soc. 2021; 143(15):5958-5966. PMC: 8215719. DOI: 10.1021/jacs.1c01565. View

Kobayashi K, Kawakami K, Kusakizako T, Miyauchi H, Tomita A, Kobayashi K . Endogenous ligand recognition and structural transition of a human PTH receptor. Mol Cell. 2022; 82(18):3468-3483.e5. DOI: 10.1016/j.molcel.2022.07.003. View

10.

Reyes M, Firat D, Hanna P, Khan M, Bruce M, Shvedova M . Substantially Delayed Maturation of Growth Plate Chondrocytes in "Humanized" Mice with the H223R Mutation of Jansen's Disease. JBMR Plus. 2023; 7(10):e10802. PMC: 10556264. DOI: 10.1002/jbm4.10802. View

11.

Fremaux J, Venin C, Mauran L, Zimmer R, Guichard G, Goudreau S . Peptide-oligourea hybrids analogue of GLP-1 with improved action in vivo. Nat Commun. 2019; 10(1):924. PMC: 6389962. DOI: 10.1038/s41467-019-08793-y. View

12.

Noda H, Guo J, Khatri A, Dean T, Reyes M, Armanini M . An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia. J Bone Miner Res. 2019; 35(3):540-549. PMC: 8050614. DOI: 10.1002/jbmr.3913. View

13.

Stewart A . Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005; 352(4):373-9. DOI: 10.1056/NEJMcp042806. View

14.

Zhao L, Ma S, Sutkeviciute I, Shen D, Zhou X, de Waal P . Structure and dynamics of the active human parathyroid hormone receptor-1. Science. 2019; 364(6436):148-153. PMC: 6929210. DOI: 10.1126/science.aav7942. View

15.

Horiuchi N, Hongo T, Clemens T . A 7-34 analog of the parathyroid hormone-related protein has potent antagonist and partial agonist activity in vivo. Bone Miner. 1991; 12(3):181-8. DOI: 10.1016/0169-6009(91)90031-t. View

16.

Cheloha R, Gellman S, Vilardaga J, Gardella T . PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol. 2015; 11(12):712-24. PMC: 4651712. DOI: 10.1038/nrendo.2015.139. View

17.

Fraser W . Hyperparathyroidism. Lancet. 2009; 374(9684):145-58. DOI: 10.1016/S0140-6736(09)60507-9. View

18.

MCKEE R, Goldman M, Caulfield M, DeHaven P, Levy J, NUTT R . The 7-34-fragment of human hypercalcemia factor is a partial agonist/antagonist for parathyroid hormone-stimulated cAMP production. Endocrinology. 1988; 122(6):3008-10. DOI: 10.1210/endo-122-6-3008. View

19.

Liu S, Jean-Alphonse F, White A, Wootten D, Sexton P, Gardella T . Use of Backbone Modification To Enlarge the Spatiotemporal Diversity of Parathyroid Hormone Receptor-1 Signaling via Biased Agonism. J Am Chem Soc. 2019; 141(37):14486-14490. PMC: 6930011. DOI: 10.1021/jacs.9b04179. View

20.

Cheloha R, Chen B, Kumar N, Watanabe T, Thorne R, Li L . Development of Potent, Protease-Resistant Agonists of the Parathyroid Hormone Receptor with Broad β Residue Distribution. J Med Chem. 2017; 60(21):8816-8833. PMC: 6016400. DOI: 10.1021/acs.jmedchem.7b00876. View