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

Schantl, A.E.; Verhulst, A.; Neven, E.; Behets, G.J.; D'Haese, P.C.; Maillard, M.; Mordasini, D.; Phan, O.; Burnier, M.; Spaggiari, D.; Decosterd, L.A.; MacAskill, M.G.; Alcaide-Corral, C.J.; Tavares, AAS; Newby, D.E.; Beindl, V.C.; Maj, R.; Labarre, A.; Hegde, C.; Castagner, B.; Ivarsson, M.E.; Leroux, J.C.

doi:10.1038/s41467-019-14091-4

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

Details

Download: 32024848_BIB_B322953EAB8C.pdf (2715.07 [Ko])
State: Public
Version: Final published version
License: CC BY 4.0

Serval ID

serval:BIB_B322953EAB8C

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

Nature communications

Author(s)

Schantl A.E., Verhulst A., Neven E., Behets G.J., D'Haese P.C., Maillard M., Mordasini D., Phan O., Burnier M., Spaggiari D., Decosterd L.A., MacAskill M.G., Alcaide-Corral C.J., Tavares AAS, Newby D.E., Beindl V.C., Maj R., Labarre A., Hegde C., Castagner B., Ivarsson M.E., Leroux J.C.

ISSN

2041-1723 (Electronic)

ISSN-L

2041-1723

Publication state

Published

Issued date

05/02/2020

Peer-reviewed

Oui

Volume

Number

Pages

721

Language

english

Notes

Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish

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 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.

Keywords

6-Phytase/metabolism, Adenine/adverse effects, Animals, Cells, Cultured, Drug Evaluation, Preclinical/methods, Dynamic Light Scattering, Ethylene Glycol/chemistry, Humans, Injections, Subcutaneous, Inositol Phosphates/chemistry, Inositol Phosphates/pharmacokinetics, Inositol Phosphates/pharmacology, Male, Muscle, Smooth, Vascular/cytology, Muscle, Smooth, Vascular/drug effects, Rats, Sprague-Dawley, Uremia/drug therapy, Uremia/physiopathology, Vascular Calcification/chemically induced, Vascular Calcification/drug therapy, X-Ray Diffraction

URN

urn:nbn:ch:serval-BIB_B322953EAB8C7

OAI-PMH

oai:serval.unil.ch:BIB_B322953EAB8C

DOI

10.1038/s41467-019-14091-4

Pubmed

32024848

Web of science

000513499700003

Open Access

Yes