A new synthetic version of the widely used anticoagulant heparin developed at the University of North Carolina at Chapel Hill can now be made in commercially viable quantities and promises to be safer than existing drugs. It is ready to begin human trials.
Researchers at the UNC Eshelman School of Pharmacy have created a synthetic form of low-molecular-weight heparin, which is typically used to treat and prevent deep vein thromboses. A DVT is a blood clot that forms in a deep vein, usually in the leg, and is dangerous because part of the clot can break off and block blood vessels in the lung causing damage or even death.
The UNC-Chapel Hill team led by Jian Liu, Ph.D., the John and Deborah McNeill, Jr. Distinguished Professor in the UNC Eshelman School of Pharmacy, has finished testing the drug for safety and effectiveness in animal models and reported their success in the Journal of Science Translational Medicine. Liu and his colleague have launched a company, Glycan Therapeutics, to explore human clinical trials.
The advantages of the UNC drug are that its simpler molecular structure should mean fewer side effects, its creators said. And unlike current options, the effects of the drug can be completely reversed with protamine if a patient experiences a problem. The most dangerous unwanted effects of LMW heparin are uncontrolled bleeding and thrombocytopenia (too few platelets in the blood). The drug is also metabolized by the liver instead of the kidneys, making it more suitable for patients with impaired kidney function.
“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” Liu said.
Heparin is a natural substance that prevents blood clotting, or coagulation, and has been in use since the late 1930s. There are three main types of heparin: unfractionated, the more highly processed low molecular weight heparin, and the synthetic fondaparinux. Natural heparin is most commonly extracted from the linings of pig intestines. It is on the World Health Organization’s List of Essential Medicines.
The natural form of the drug was in the spotlight in spring 2008 when more than 80 people died and hundreds of others suffered bad reactions after taking it, leading to recalls of heparin in countries around the world. Authorities linked the problems to a contaminant in raw natural heparin from China.
Synthesizing heparin, rather than extracting it from animals, allows more control over its anticoagulant properties and creates a purer, safer, more reliable drug, Liu said.
“The pig stuff has served us well for almost 100 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Liu says. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”
Co-authors and Funding
This work is supported by the National Institutes of Health, the Eshelman Institute for Innovation and the North Carolina Translational and Clinical Sciences Institute.
- Yongmei Xu, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, UNC-Chapel Hill;
- Kasemsiri Chandarajoti, Division of Hematology/Oncology, Department of Medicine, University of North Carolina, and Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Thailand;
- Xing Zhang, Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute
- Vijayakanth Pagadala, †, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, UNC-Chapel Hill;
- Wenfang Dou, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, UNC-Chapel Hill;
- Debra Moorman Hoppensteadt, Department of Pathology, Loyola University Medical Center
- Erica Sparkenbaugh, Division of Hematology/Oncology, Department of Medicine, UNC-Chapel Hill;
- Brian Cooley, Department of Pathology and Laboratory Medicine, School of Medicine, UNC-Chapel Hill;
- Sharon Daily, Center for Global Health, RTI International
- Nigel S. Key, Division of Hematology/Oncology, Department of Medicine, UNC-Chapel Hill;
- Diana Severynse-Stevens, Center for Global Health, RTI International
- Jawed Fareed, Department of Pathology, Loyola University Medical Center
- Robert J. Linhardt,*, Department of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute
- Rafal Pawlinski,* Division of Hematology/Oncology, Department of Medicine, UNC-Chapel Hill; and
- Jian Liu,* Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, UNC-Chapel Hill.