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- Title
Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.
- Authors
Schantl, Antonia E.; Verhulst, Anja; Neven, Ellen; Behets, Geert J.; D'Haese, Patrick C.; Maillard, Marc; Mordasini, David; Phan, Olivier; Burnier, Michel; Spaggiari, Dany; Decosterd, Laurent A.; MacAskill, Mark G.; Alcaide-Corral, Carlos J.; Tavares, Adriana A. S.; Newby, David E.; Beindl, Victoria C.; Maj, Roberto; Labarre, Anne; Hegde, Chrismita; Castagner, Bastien
- 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. Cardiovascular calcification is a serious pathology for which effective pharmacological treatments are lacking. Here the authors show that an optimized oligo(ethylene glycol) derivative of inositol phosphate interferes with calcium phosphate crystallization and inhibits soft tissue calcification in vivo following subcutaneous injection.
- Subjects
INOSITOL phosphates; CALCIFICATION; CALCIUM phosphate; DISCONTINUOUS precipitation; SUBCUTANEOUS injections; CELL culture; PHYTIC acid; ETHYLENE glycol
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-14091-4