Mimicking protamine without the allergic reaction

Protamine – a natural drug extracted from shell fish – is used to remove anti-clotting drug heparin from the blood. However it can have serious side effects in some patients.

Chemists from the University of York have designed a synthetic molecule capable of binding heparin – which is given to surgery patients to thin the blood and prevent clotting – just as effectively as protamine, but without the undesirable side effects.

The synthetic molecules are designed to self-assemble into nanometre-sized structures with similar dimensions to protamine and containing multiple heparin binding units.

“Our binder is a small molecule, which spontaneously self-assembles into spheres with a similar size and charge density to protamine itself,” Professor Dave Smith told Laboratory News. “As such, our system mimics the structure of protamine.  We could actually see the binding of our spherical self-assembled protamine mimic along the heparin polymer chains using electron microscopy.”

Early studies show the nano-systems are capable of binding to heparin as effectively as protamine.

“Because our heparin binder is self-assembled, rather than being a fixed polymer (like protamine or synthetic heparin binders), it can also disassemble,” Smith said. “Furthermore, because we have constructed the molecule using ester linkages, the individual molecules also have the capacity to degrade under biological conditions.  We hope that these factors will mean that our system shows lower toxicity and greater biocompatibility than other heparin binders.”

The worst side effect of protamine is anaphylaxis, although there are also a number of milder reactions. In a key study, 233 patients out of about 2,700 had some kind of adverse event after protamine treatment – around 10%, Smith said. Not all of these could be definitively linked to protamine, but there were 11 definite severe cases, and 42 moderately severe (about 2% of patients overall) which could be connected to the protamine.  In severe cases the protamine-induced allergy is often associated with morbidity and mortality

 “A significant number of studies now need to be done; structure optimisation; activity in plasma/blood – effect on blood clotting assays; toxicity studies/animal studies,” said Smith “It would then go into human clinical development and trials (which is an extended process). We are here at the first fundamental steps in taking a different strategy to heparin binding.”