Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32024848.
- Also identified by DOI 10.1038/s41467-019-14091-4 and PMC identifier 7002685.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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), (OEG<sub>2</sub>)<sub>2</sub>-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG<sub>2</sub>)<sub>2</sub>-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<sub>2</sub>)<sub>2</sub>-IP4 disrupts the nucleation and growth of pathological calcification.
Medical subject headings
- Inositol Phosphates
- Vascular Calcification