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For years, scientists have wanted to create a cheap and easy-to-make synthetic version of heparin, a powerful blood thinner derived from pig intestines and cow lungs. If there is a disease outbreak or something else interferes with livestock supplies, heparin could become more expensive than it already is.
A synthetic version of the drug would also be purer and safer than a compound derived from animals. Doctors could better control the blood thinning properties of a synthetic drug and limit side effects during medical procedures such as heart surgery, kidney dialysis, stent implantation and hip and knee replacement.
There is just one catch. The only synthetic heparin on the market contains a complex element called iduronic acid, a single sugar unit that is difficult to replicate but was believed to be integral to heparin’s anticoagulation effects. Making sure that iduronic acid is part of the synthetic heparin molecule takes 11 time-consuming steps, making the drug much more expensive than naturally derived heparin.
UNC chemist Jain Liu knows this; every chemist who works with synthetic heparin knows this. But one day last year Liu, associate professor in the School of Pharmacy, asked his associate, visiting professor Jinghua Chen, to see what happens if synthetic heparin is made without iduronic acid.
Chen ran the experiment, got the results and then sprinted down the hall to Liu’s office. “We don’t need the iduronic acid,” Chen said.
“You’ve got to be kidding me,” Liu responded.
They reran the experiment and their new synthetic heparin, sans iduronic acid, maintained its anticoagulant property.
“This was very surprising,” Liu said. “We ran the experiment several more times, and we noticed that when you have a small fragment of the heparin molecule, indeed you do need that iduronic acid. But when you grow the fragment to a certain size, turns out that the molecule doesn’t need the iduronic acid to work as an anticoagulant.”
Liu said that leaving out iduronic acid made the molecule’s structure half as complex. He said that scientists had always tried to make synthetic heparin, which is a polysaccharide, by creating the smallest molecule possible because chemically connecting more than two monosaccharide units is a difficult process.
“When making this molecule, chemists have to make a certain type of linkage for these sugar units so that the molecule has the right biological activity,” he said.
In this case, that activity is anticoagulation. But it turns out that making a larger molecule is far easier because the iduronic acid is not needed.
Liu and Chen do not know why it is not needed; they just know that the larger molecule works as an anticoagulant, and the fact that the larger molecule is heavier does not matter much either.
Also, Liu added an enzyme that allowed him to prepare the compound without iduronic acid, making it much easier to create a version of heparin that is more pure. And such purity ensures that the compound has a very strong blood thinning property.
Liu patented his new discovery — a drug called Recomparin — and is working with the Office of Technology Development to finalize a licensing agreement with a pharmaceutical company and begin the process of gaining approval from the Food and Drug Administration.
Note: Jinghua Chen has returned to Wuhan University of Technology in China. Graduate student Courtney Jones co-authored a paper on this research for the September issue of the journal Chemistry and Biology.
Writer: Mark Derewicz
Editor: Neil Caudle