Prolonging parathyroid hormone analog action in vitro and in vivo through peptide lipidation

Parathyroid hormone (PTH) analogs with improved actions in vivo could lead to optimized treatments for bone and mineral ion diseases. Rapid clearance from the circulation and short dwell times on the PTH receptor limit the efficacies of conventional PTH peptides currently in medical use. Here, we seek to enhance PTH peptide efficacy using two distinct peptide lipidation strategies. First, we append a lipid chain to the peptide's C-terminus in a fashion to promote binding to serum albumin and hence prolong the peptide's circulation half-life in vivo. Second, we append a lipid chain to a lysine side chain in a fashion designed to anchor the peptide to the cell membrane as the ligand is bound to the receptor and hence increase its dwell time on the receptor. We find that both strategies of lipidation can profoundly enhance the efficacy of PTH peptides in vitro and in mice. Our results could lead to the development of modified PTH analogs with optimized therapeutic utility.

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Publication Details

Journal
Nature Communications
Published
2025-05-14
DOI
https://doi.org/10.1038/s41467-025-59665-7
Citations
5
Primary Topic
Metabolism, Diabetes, and Cancer
Type
article
Field-Weighted Citation Impact
4.03

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Prolonging parathyroid hormone analog action in vitro and in vivo through peptide lipidation

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Prolonging parathyroid hormone analog action in vitro and in vivo through peptide lipidation

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article en
5 citations

Abstract

Parathyroid hormone (PTH) analogs with improved actions in vivo could lead to optimized treatments for bone and mineral ion diseases. Rapid clearance from the circulation and short dwell times on the PTH receptor limit the efficacies of conventional PTH peptides currently in medical use. Here, we seek to enhance PTH peptide efficacy using two distinct peptide lipidation strategies. First, we append a lipid chain to the peptide's C-terminus in a fashion to promote binding to serum albumin and hence prolong the peptide's circulation half-life in vivo. Second, we append a lipid chain to a lysine side chain in a fashion designed to anchor the peptide to the cell membrane as the ligand is bound to the receptor and hence increase its dwell time on the receptor. We find that both strategies of lipidation can profoundly enhance the efficacy of PTH peptides in vitro and in mice. Our results could lead to the development of modified PTH analogs with optimized therapeutic utility.

Nature CommunicationsVol. 16(1)
University of Wisconsin–Madison (US), Harvard University (US), Massachusetts General Hospital (US), National Institute of Diabetes and Digestive and Kidney Diseases (US), Chugai Pharma (United States) (US), MaineGeneral Medical Center (US)
Deutsche Forschungsgemeinschaft, National Institutes of Health
Zero hunger
Openalex Percentile: Top 6%
Metabolism, Diabetes, and Cancer
4.03
DOIOpen Access PDFOpenAlex
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