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

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.

Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

“…Leveraging our expertise in IP6 engineering [ 29,30,38,39 ] and the implementation of an image‐based screening approach enabled us to rapidly assess the effect of different modifications on the dynamics of CaOx crystallization under simulated pathophysiological conditions. The activity of IP6 analogues was highly dependent on the number of negative charges of the molecule, presumably being the driving force of binding between Ca 2+ ions on the crystal surface and the molecules, thereby leading to inhibition of crystal growth.…”

“…[ 27,28 ] Substituting phosphate groups with different anionic groups or oligo‐ethylene glycol (OEG) chains led to the development of molecules with increased stability against enzymatic degradation, tunable calcium binding properties, [ 29 ] and enhanced inhibition of calcium phosphate crystallization. [ 30 ] Thus, we hypothesized that the described molecules might provide a promising starting point for the engineering of potent renal CaOx inhibitors.…”

Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020

“…A number of novel therapeutic agents to counteract ectopic mineralization are currently in preclinical or early clinical testing. Such molecules include inositol hexaphosphate (INS-3001) and myo-inositol hexaphosphate (SNF472), potential inhibitors of ectopic mineralization [ 82 , 83 ] but whether they will elicit reversal of the existing mineral deposits is currently unknown. In addition, although transient, the efficacy of intravenous sodium thiosulfate in dissolution of ectopic calcification was demonstrated in one PXE patient with severe early-onset manifestations [ 56 ].…”

Cardiovascular complications of chronic kidney disease: pioneering studies

“…16 A major persistent issue is its treatment, prevention, and potential regression. 17,18 Because calcium and phosphate overload are major contributors to cardiovascular calcification in CKD, Chertow et al conducted a randomized controlled trial comparing sevelamer, a calcium-free nonabsorbed polymer, with calcium-based phosphate binders in 200 prevalent chronic hemodialysis patients. 15 Study outcomes included biochemical parameters (serum phosphorus, calcium, and intact parathyroid hormone) and calcification of the coronary arteries and thoracic aorta using a calcification score derived from electron beam tomography.…”

“…20 Many other approaches to halt progress of cardiovascular calcifications in CKD have been proposed or are under investigation. 16,18 Figure 5 is adapted with permission from Chertow GM, Burke SK, Raggi P, et al Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int.…”