They observed that naked-UHRA (variant of UHRA lacking mPEG chains) has similar binding profiles to protamine. Using isothermal calorimetry, the group studied the contribution of mPEG chains in UFH-antidote interaction. Unlike protamine, the positive charges at the core of UHRA are shielded by the mPEG chains that avert non-specific interactions with blood proteins and provide selectivity toward heparins. The positive charges on the protamine peptide are exposed, which renders it prone to bind nonspecifically to other negatively charged proteins in the blood. Kalathottukaren and team discuss how the rational design of UHRA makes it a better and non-toxic antidote to heparins compared to protamine. In the paper published in Biomacromolecules, 1 Dr. Also, UHRA can reverse all the clinically used heparins. Compared to protamine, UHRA can be used in a wide range of doses and is highly biocompatible. UHRA has two major structural components: a hyperbranched polyglycerol core decorated with positive charges and a brush layer of methoxypolyethylene glycol (mPEG) chains (Figure 1). The Kizhakkedathu and Haynes labs have previously developed a superior antidote to heparins called Universal Heparin Reversal Agent (UHRA). Secondly, protamine is only able to completely neutralize unfractionated heparin (UFH) it has a moderate antidote activity towards low molecular weight heparins (LMWHs) and no activity against Fondaparinux. At higher doses, protamine binds non-specifically to blood proteins and shows some anticoagulant effects. Firstly, it has only a small range of doses where it can effectively neutralize heparins.

Protamine is a positively charged peptide that binds to negatively charged heparin via electrostatic interactions. The only FDA approved heparin antidote is protamine sulphate (protamine). Hence, it is important to be able to neutralize heparins. Although heparins are effective in preventing blood clots, the risk of bleeding associated with their use is a major clinical concern. In spite of the introduction of anti-Xa and anti-thrombin agents to treat/prevent thrombosis, heparin continues to be used in major surgeries like cardio-pulmonary bypass to prevent blood clotting. They were the primary agents used to treat deep vein thrombosis, arterial thromboembolism, and ischemic stroke.

Historically, heparins were the mainstay of anticoagulant therapy. By Sreeparna Vappala, Graduate Student, Kizhakkedathu Lab

Protamine sulfate antidote