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Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers

Author

Listed:
  • Antonia E. Schantl

    (ETH Zurich)

  • Anja Verhulst

    (University of Antwerp)

  • Ellen Neven

    (University of Antwerp)

  • Geert J. Behets

    (University of Antwerp)

  • Patrick C. D’Haese

    (University of Antwerp)

  • Marc Maillard

    (Lausanne University Hospital)

  • David Mordasini

    (Lausanne University Hospital)

  • Olivier Phan

    (Lausanne University Hospital)

  • Michel Burnier

    (Lausanne University Hospital)

  • Dany Spaggiari

    (Lausanne University Hospital)

  • Laurent A. Decosterd

    (Lausanne University Hospital)

  • Mark G. MacAskill

    (University of Edinburgh)

  • Carlos J. Alcaide-Corral

    (University of Edinburgh)

  • Adriana A. S. Tavares

    (University of Edinburgh)

  • David E. Newby

    (University of Edinburgh)

  • Victoria C. Beindl

    (ETH Zurich)

  • Roberto Maj

    (Inositec Inc.)

  • Anne Labarre

    (McGill University)

  • Chrismita Hegde

    (McGill University)

  • Bastien Castagner

    (McGill University)

  • Mattias E. Ivarsson

    (Inositec Inc.)

  • Jean-Christophe Leroux

    (ETH Zurich)

Abstract

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG2)2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG2)2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG2)2-IP4 disrupts the nucleation and growth of pathological calcification.

Suggested Citation

  • Antonia E. Schantl & Anja Verhulst & Ellen Neven & Geert J. Behets & Patrick C. D’Haese & Marc Maillard & David Mordasini & Olivier Phan & Michel Burnier & Dany Spaggiari & Laurent A. Decosterd & Mark, 2020. "Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14091-4
    DOI: 10.1038/s41467-019-14091-4
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