Nature communications · 2020
Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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, Ivarsson Mattias E, Leroux Jean-Christophe
Аннотация
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.