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

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 G. MacAskill, Carlos J. Alcaide-Corral, Adriana A. S. Tavares, David E. Newby, Victoria C. Beindl, Roberto Maj, Anne Labarre, Chrismita Hegde, Bastien Castagner, Mattias E. Ivarsson () and Jean-Christophe Leroux ()
Additional contact information
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

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14091-4

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