Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.
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5 février 2020
- doi: 10.1038/s41467-019-14091-4
- issn: 2041-1723
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info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-019-14091-4
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info:eu-repo/semantics/altIdentifier/pmid/32024848
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info:eu-repo/semantics/altIdentifier/eissn/2041-1723
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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_B322953EAB8C7
info:eu-repo/semantics/openAccess , CC BY 4.0 , https://creativecommons.org/licenses/by/4.0/
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Mesoinositol Myoinositol CyclohexanehexolCiter ce document
A.E. Schantl et al., « Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers. », Serveur académique Lausannois, ID : 10.1038/s41467-019-14091-4
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Résumé
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), (OEG 2 ) 2 -IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG 2 ) 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 (OEG 2 ) 2 -IP4 disrupts the nucleation and growth of pathological calcification.