serval:BIB_B322953EAB8C
Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.
10.1038/s41467-019-14091-4
000513499700003
32024848
Schantl
A.E.
author
Verhulst
A.
author
Neven
E.
author
Behets
G.J.
author
D'Haese
P.C.
author
Maillard
M.
author
Mordasini
D.
author
Phan
O.
author
Burnier
M.
author
Spaggiari
D.
author
Decosterd
L.A.
author
MacAskill
M.G.
author
Alcaide-Corral
C.J.
author
Tavares
AAS
author
Newby
D.E.
author
Beindl
V.C.
author
Maj
R.
author
Labarre
A.
author
Hegde
C.
author
Castagner
B.
author
Ivarsson
M.E.
author
Leroux
J.C.
author
article
2020-02-05
Nature communications
2041-1723
2041-1723
journal
11
1
721
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.
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
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
University of Lausanne
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