Engineered Design of Polymers for neutralizing the Effects of the Anticoagulant Fondaparinux

Abstract

Anticoagulation by using unfractionated heparin (UFH) and heparin derivatives is an essential clinical practice in modern medicine. Overdose of these medications can lead to life-threatening bleeding episodes. Currently, no antidote is available to effectively neutralize new anticoagulant medications. Fondaparinux is one of the medications that have become increasingly important in clinical medicine. The synthetic polymer HBSPCM has been found to be a promising antidote for fondaparinux. The optimal HBSPCM will bind fondaparinux with high affinity, neutralizing it. The approach for this paper is to develop a robust model capable of predicting an improved design for HBSPCM to efficiently neutralize fondaparinux. A modified Debye-Hückel energy equation is used to calculate the electrostatic rate enhancement of the association reaction of the HBSPCM-fondaparinux complex. However, this equation requires the knowledge of certain physical parameters, which are known for fondaparinux but that need to be estimated for HBSPCM and the fondaparinux-HBSPCM complex. Molecular dynamics simulations among other techniques are used to characterize these molecules. Once these parameters are known, a program that simulates different extensions of HBSPCM for the initial design of the antidote can be developed. In this paper, the number of the binding cationic units attached to the surface of HBSPCM will be the variable modified by the mathematical model. Isothermal titration calorimetry (ITC) and electrophoresis experiments are used to validate the predictions of the model.