Researchers at Rensselaer Polytechnic Institute and the University of North Carolina at Chapel Hill (UNC) have created a synthetic form of low-molecular-weight heparin that can be reversed in cases of overdose and would be safer for patients with poor kidney function.
“We took this drug and not only made it cost effectively, but we’ve also improved the properties of the drug,” said Robert Linhardt, the Ann and John H. Broadbent Jr. ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering, a member of the Rensselaer Center for Biotechnology and Interdisciplinary Studies (CBIS), and one of the inventors of the new drug. “The synthetic version that we’ve made is reversible, it can be used in renal patients, and it doesn’t come from animals, which is a critical advance in safety.”
Heparin is an anticoagulant, and is most commonly extracted from pig intestines in two forms: unfractionated heparin, which is commonly used in procedures such as dialysis, and a more-refined low-molecular-weight (LMW) heparin, which is used around the world for preventing dangerous blood clots. A team led by Linhardt and Jian Liu, a professor in the UNC Eshelman School of Pharmacy, created a synthetic version of LMW heparin for which there is an existing antidote. Their creation is described in an article published online February 23 in the journal Nature Chemical Biology.
Linhardt and Liu used a chemo-enzymatic process to synthesize the drug, an approach they developed in research on a simpler anticoagulant drug published in Science in October 2011. Synthesizing LMW heparin allowed them to make many improvements on the animal-derived form of the drug currently available. Linhardt’s research supports the Rensselaer School of Science interdisciplinary theme of biomedical science and applications, and is part of a research focus on biocatalysis and metabolic engineering within CBIS. His research on LMW heparin was funded by the National Institutes of Health.
Up to 5 percent of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing Federal Drug Administration-approved antidote (protamine) available. Protamine is not as effective in reversing naturally derived LMW heparin, so Linhardt and Liu engineered their drug’s molecular structure so that protamine is able to deactivate it.
Naturally produced LMW heparin is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system, a relatively common condition among patients requiring anticoagulation. Linhardt and Liu made additional changes allowing their drug to bind to receptors that clear it through the liver.
LMW heparin makes up more than half the U.S. market for heparin. Linhardt and Liu said the new version they created is a safe, economically viable alternative to the existing animal-derived supply. But the new drug would require FDA approval, and would probably also undergo alteration on the path to market.
“This is a discovery target. The process that we’ve