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Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides

Author

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  • Alessandro Zorzi

    (Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Simon J. Middendorp

    (Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Jonas Wilbs

    (Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Kaycie Deyle

    (Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Christian Heinis

    (Institute of Chemical Sciences and Engineering, School of Basic Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL))

Abstract

The rapid renal clearance of peptides in vivo limits this attractive platform for the treatment of a broad range of diseases that require prolonged drug half-lives. An intriguing approach for extending peptide circulation times works through a ‘piggy-back’ strategy in which peptides bind via a ligand to the long-lived serum protein albumin. In accordance with this strategy, we developed an easily synthesized albumin-binding ligand based on a peptide-fatty acid chimera that has a high affinity for human albumin (Kd=39 nM). This ligand prolongs the elimination half-life of cyclic peptides in rats 25-fold to over seven hours. Conjugation to a peptide factor XII inhibitor developed for anti-thrombotic therapy extends the half-life from 13 minutes to over five hours, inhibiting coagulation for eight hours in rabbits. This high-affinity albumin ligand could potentially extend the half-life of peptides in human to several days, substantially broadening the application range of peptides as therapeutics.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms16092
    DOI: 10.1038/ncomms16092
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    Cited by:

    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. 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.

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