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Abstract: TH-PO379

PEGylation of Inositol Hexaphosphate (InsP6) Decreases Its Binding Affinity for Hydroxyapatite and Its Capacity to Inhibit Plasma Calcification In Vitro

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Perez, Maria del mar, Sanifit Therapeutics, Palma, Spain
  • Ferrer, Miquel D., Sanifit Therapeutics, Palma, Spain
  • Ortega-Castro, Joaquin, Universitat de les Illes Balears, Palma, Spain
  • Bassissi, Firas, Sanifit Therapeutics, Palma, Spain
  • Perelló, Joan, Sanifit Therapeutics, Palma, Spain
  • Salcedo, Carolina, Sanifit Therapeutics, Palma, Spain
Background

Vascular calcification (VC) is a major contributor to increased morbidity and mortality in Chronic Kidney Disease patients undergoing dialysis. Although VC is a multifactorial process, the final common pathway is deposition of solid hydroxyapatite (HAP) within the arteries. SNF472, a salt of InsP6, is a selective calcification inhibitor that interferes in the formation and growth of ectopic HAP. SNF472 is currently being developed for the treatment of calciphylaxis in patients on dialysis. Inositol-1,2,3,5-tetraphosphate-4,6-bisPEG100 (InsP4bisPEG) is an inositol phosphate derivative resulting from the PEGylation of inositol tetraphosphate (InsP4) with polyethylene glycol (PEG) 100. Our aim was to study the binding affinities of SNF472, InsP4bisPEG and InsP4 for the HAP surface, and its relationship with their in vitro efficacy by inhibiting calcium phosphate crystallization.

Methods

To evaluate the adsorption binding affinity (Eads) of SNF472, InsP4bisPEG and InsP4 to the HAP crystal surface, computational studies were performed using Density Functional Theory calculations with DMOL3 (MS2016). The in vitro efficacy of InsP4bisPEG and InsP4 was evaluated using a pharmacodynamic assay to measure the plasma calcification potential using a previously validated spectrophotometric method, and compared to SNF472 in the 0-100 µM range.

Results

Molecular modelling revealed that SNF472 binds to the HAP surface with higher affinity than InsP4bisPEG, as revealed by their relative energies of absorption taking InsP4 as reference (ΔEads=-110 kcal/mol for SNF472 and ΔEads=-41.1 kcal/mol for InsP4bisPEG). These results are correlated with the inhibition potencies observed in the human plasma HAP crystallization assay. EC50 was 2.2 µM, 3.8 µM and 8.5 µM, for SNF472, InsP4bisPEG and InsP4, respectively.

Conclusion

SNF472 shows the highest binding affinity and the highest in vitro potency in the inhibition of HAP crystallization in human plasma, which is concordant with the larger electrostatic interactions between SNF472 and HAP, since it is a more charged molecule.

Funding

  • Commercial Support