Faculty Spotlight: Jian Liu, PhD

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Faculty Spotlight: Jian Liu, PhD

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The blood-thinner heparin is one of the world’s best-selling drugs. The annual worldwide sales of heparin are estimated at $3 billion. It is also a difficult drug to produce consistently because it is a naturally occurring substance extracted from animal organs, primarily the intestinal lining of pigs. The drug was in the spotlight in 2008 when more than eighty people died and hundreds of others suffered adverse reactions to it, leading to recalls of the drug in countries around the world. Authorities linked the problems to a contaminant in raw natural heparin made from pigs in China.

A synthetic version of heparin that can be produced in controlled conditions is key to preventing a recurrence of that tragedy, says Jian Liu, PhD, an associate professor at the UNC Eshelman School of Pharmacy who is working to develop easier ways to make synthetic heparin.

“The pig stuff has served us well for 50 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.”

More Is Better

Researchers at MIT were the first to develop a process for producing synthetic heparin, but they were only able to produce it in amounts less than one microgram (one human dose of heparin is approximately 100 milligrams). Liu and his colleagues, however, synthesized hundreds of milligrams of heparin by developing a large-scale process involving engineered enzymes and co-factor recycling.

“Synthesizing heparin chemically is extremely difficult, but by doing so, we eliminate the risk of viruses and other forms of contamination and improve the safety of a widely used drug,” Liu says. “It gives us a cleaner compound. Our process mimics the existing process of extracting heparin from animal organs, so the synthetic version has very similar anticoagulant effect and can be metabolized in the body to maintain low drug toxicity.”

The researchers say their new, scaleable process can be applied to synthesize other heparin-based structures for regulating cell growth and may have applications in wound healing or cancer treatment. The process can also be used as a tool for screening lead compounds with heparin-like structures for drug discovery.

Research in Liu’s group in the School’s Division of Chemical Biology and Medicinal Chemistry focuses on the study of sulfated carbohydrates like heparin. Using recombinant biosynthetic enzymes, researchers design the structure of heparin to improve the anticoagulant activity and explore the antiviral and anticancer activities.

Liu collaborated on the interdisciplinary project with Robert Linhardt, a professor of biocatalysis and metabolic engineering at Rensselaer Polytechnic Institute. UNC-Chapel Hill and Rensselaer have jointly filed a provisional patent on the process.

Less Is Better

In 2007, Liu and his colleagues made another big stride in making heparin easier to produce. They created a synthetic version of the drug, Recomparin, that has a simpler chemical structure. They removed a complex component, a single sugar called iduronic acid that is difficult to replicate, from the heparin molecule without altering the drug’s function as an anticoagulant.

“We proved we don’t really need that structure for the anticoagulant effect,” Liu said. “By eliminating the iduronic acid unit, we were able to reduce the structural complexity of the heparin molecule by approximately 50 percent.”

Recomparin is also expected to reduce dangerous side effects, such as uncontrolled bleeding, while providing the same benefits as naturally derived heparin.

The next step for Recomparin will be to find a company to license the drug and begin the process of getting approval from the Food and Drug Administration.

Customizable Heparin

In 2008, Liu and his colleagues developed a way to modify the enzyme heparan sulfate 2-O-sulfotransferase, which produces heparin in the human body in addition to other heparin-like molecules. By modifying 2-O-sulfotransferase, researchers will be able to create customized forms of synthetic heparin with different properties.

“Previously it was nearly impossible to change the nature of the heparin generated by the enzyme,” Liu says. “The degree of difficulty was ten-plus. Now it’s more like a two or three, which opens the door to the possibility of improving on the natural product.”

There is also interest in heparin as a treatment for small-cell lung cancer, Liu says. Being able to produce customized versions of the heparin molecule using 2-O-sulfotransferase would allow researchers to emphasize the drug’s potential anti-cancer properties. Heparin-like structures have also shown potential as treatments for arthritis, asthma, and transplant rejection, among other conditions.

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