IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59665-7.html
   My bibliography  Save this article

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

Author

Listed:
  • Jakob Höppner

    (and Harvard Medical School)

  • Hiroshi Noda

    (and Harvard Medical School
    Chugai Pharmaceutical Co., Ltd.)

  • Anju Krishnan Anitha

    (and Harvard Medical School)

  • Ross W. Cheloha

    (University of Wisconsin-Madison
    and Kidney Diseases; National Institutes of Health)

  • Thomas Dean

    (and Harvard Medical School)

  • Michael Bruce

    (and Harvard Medical School)

  • Daniel J. Brooks

    (and Harvard Medical School)

  • Michael Mannstadt

    (and Harvard Medical School)

  • Mary L. Bouxsein

    (and Harvard Medical School)

  • Samuel H. Gellman

    (University of Wisconsin-Madison)

  • Ashok Khatri

    (and Harvard Medical School)

  • Harald Jüppner

    (and Harvard Medical School
    and Harvard Medical School)

  • Thomas J. Gardella

    (and Harvard Medical School)

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.

Suggested Citation

  • Jakob Höppner & Hiroshi Noda & Anju Krishnan Anitha & Ross W. Cheloha & Thomas Dean & Michael Bruce & Daniel J. Brooks & Michael Mannstadt & Mary L. Bouxsein & Samuel H. Gellman & Ashok Khatri & Haral, 2025. "Prolonging parathyroid hormone analog action in vitro and in vivo through peptide lipidation," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59665-7
    DOI: 10.1038/s41467-025-59665-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59665-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-59665-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Alessandro Zorzi & Simon J. Middendorp & Jonas Wilbs & Kaycie Deyle & Christian Heinis, 2017. "Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides," Nature Communications, Nature, vol. 8(1), pages 1-9, December.
    2. Xiuwen Zhai & Chunyou Mao & Qingya Shen & Shaokun Zang & Dan-Dan Shen & Huibing Zhang & Zhaohong Chen & Gang Wang & Changming Zhang & Yan Zhang & Zhihong Liu, 2022. "Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Fenghui Zhao & Qingtong Zhou & Zhaotong Cong & Kaini Hang & Xinyu Zou & Chao Zhang & Yan Chen & Antao Dai & Anyi Liang & Qianqian Ming & Mu Wang & Li-Nan Chen & Peiyu Xu & Rulve Chang & Wenbo Feng & T, 2022. "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Dongya Zhang & Sidan Tian & Yanjie Liu & Meng Zheng & Xiangliang Yang & Yan Zou & Bingyang Shi & Liang Luo, 2022. "Near infrared-activatable biomimetic nanogels enabling deep tumor drug penetration inhibit orthotopic glioblastoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Jeffrey Y. K. Wong & Arunika I. Ekanayake & Serhii Kharchenko & Steven E. Kirberger & Ryan Qiu & Payam Kelich & Susmita Sarkar & Jiaqian Li & Kleinberg X. Fernandez & Edgar R. Alvizo-Paez & Jiayuan Mi, 2023. "Genetically encoded discovery of perfluoroaryl macrocycles that bind to albumin and exhibit extended circulation in vivo," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Shivani Sachdev & Brendan A. Creemer & Thomas J. Gardella & Ross W. Cheloha, 2024. "Highly biased agonism for GPCR ligands via nanobody tethering," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Christoph Klenk & Maria Scrivens & Anina Niederer & Shuying Shi & Loretta Mueller & Elaine Gersz & Maurice Zauderer & Ernest S. Smith & Ralf Strohner & Andreas Plückthun, 2023. "A Vaccinia-based system for directed evolution of GPCRs in mammalian cells," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    5. Yan Chen & Qingtong Zhou & Jiang Wang & Youwei Xu & Yun Wang & Jiahui Yan & Yibing Wang & Qi Zhu & Fenghui Zhao & Chenghao Li & Chuan-Wei Chen & Xiaoqing Cai & Ross A .D. Bathgate & Chun Shen & H. Eri, 2023. "Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Ashan Wijesinghe & Sarika Kumari & Valerie Booth, 2022. "Conjugates for use in peptide therapeutics: A systematic review and meta-analysis," PLOS ONE, Public Library of Science, vol. 17(3), pages 1-19, March.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59665-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.