Heparin is one of the most prescribed therapeutics in modern medicine, coming second only to insulin. The blood thinning agent is used widely in surgeries, dialysis, and other vascular treatments. While the drug is extremely effective, dose requirements can be unpredictable, leading to excessive bleeding when over administered. The current reversal agent or ‘antidote’ for excess heparin is protamine, a positively charged protein isolated from salmon milt. However, the structure of protamine is only able to inhibit certain heparin strains, resulting in a narrow therapeutic window for the antidote. Members of the Kizhakkedathu research group have made a breakthrough in the development of an effective universal heparin reversal agent (UHRA) using a multivalent synthetic polymer.
The antidote is showcased in the October 29th issue of Science: Translational Medicine. Experiments were designed to elucidate the mode of action and efficacy of the newly developed antidote. While the surface of UHRA bears the same heparin binding groups as protamine, the attached polymer scaffold offers an advantage as the density and number of binding groups can be easily manipulated using chemical synthesis. Multivalency, or inserting multiple binding groups on one scaffold, is particularly effective as cooperative binding behavior can be achieved. Through isothermal titration calorimetry, these features were optimized to exhibit high binding affinity without compromising biocompatibility. Being fully synthetic, the therapeutic is cost-effective with significantly reduced batch-to-batch variation in comparison to Protamine. The researchers believe that the use of this new drug, possessing universal reversal capabilities, would be most effective in time sensitive high-risk surgeries. The laboratory is currently planning to conduct trials in larger organisms before attempting the first set of human trials.
Using simplified, bio-inspired polymers as a solution to a complex biological problem is what Dr. Kizhakkedathu is quickly becoming known for in the scientific community. The work of his research group has garnered well-deserved attention, most prominently in Chemical and Engineering News.
This research was funded by the Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada (NSERC).
Article contributed by Erika Siren, PhD Student at Kizhakkedathu Lab, CBR