Tufts-developed compound may be safer way to prevent blood clots
by C.W. Wolff

A team of Tufts biomedical researchers has built a new type of compound that might some day be more effective—and safer—than existing blood thinners used to prevent life-threatening blood clots.

The compounds, called pepducins, also may offer new approaches for treating a variety of other diseases, including diabetes, inflammatory bowel disease and asthma. And they may serve to help scientists better understand how cells receive messages from the outside.

Dr. Athan Kuliopulos and Dr. Lidija Covic © Mark Morelli

Pepducins were built by Dr. Athan Kuliopulos, associate professor of medicine and biochemistry, and Dr. Lidija Covic, assistant professor of medicine. Kuliopulos directs the Hemostasis and Thrombosis Laboratory at Tufts-New England Medical Center.

Their research, reported in the Proceedings of the National Academy of Sciences and in Nature Medicine, has caused a stir in the pharmaceutical world.

Anyone who has used, or knows someone who has used, classic blood thinners is aware they are difficult to regulate, have side effects and can lead to hemorrhaging or liver damage.

These drugs work by hindering the production of thrombin, a molecule that delivers the "start clotting" signal to the platelets—blood cells essential in the coagulation process. Thrombin also triggers the production of fibrin, the netting in blood clots. When thrombin is eliminated, all parts of the coagulation process are eliminated.

A better approach would be to block the thrombin message from getting into the platelet cells. Blocking cell surface receptors is how many drugs work and, in the case of anti-coagulants, would allow the thrombin to carry out at least some of its clot-related tasks. However, numerous attempts to design a thrombin receptor blocker have failed, according to Kuliopulos.

He decided to focus "farther downstream"—find a way to block the thrombin signals inside the cell, just on the other side of the cell membrane. "Interestingly, it was easier to design a molecule to block the signal inside the cell than it's proven to be to design one for the outside surface," says Kuliopulos, although why is not clear.

Pepducins are lipidated peptides—protein molecules (peptides) attached to a fatty (lipid) substance similar to cell membranes. Lipidated peptides were developed in the late 1980s but not for the use Kuliopulos' research team had in mind.

To use the lipidated peptides for blocking an incoming signal, the team had to find a way to keep the peptide near the receptor site inside the cell. They did this by "tethering" it to the lipid, something, according to Kuliopulos, that had not been done before.

Kuliopulos' pepducins hinder platelets from playing their full role in clotting—a role that includes production of sticky clots that adhere to the sides of blood vessels and can cause strokes. "You can still have blood clotting using the pepducin," says Kuliopulos. "But the clots won't effectively stick to blood vessel walls." And, at least in animal experiments, there are no apparent side effects.

Kuliopulos' research team is now investigating whether pepducins might be designed to address inflammatory bowel disease, for which no drugs currently exist. The researchers also want to look at designing pepducins that could turn on—rather than block—certain signals, possibly for use in treating diabetes and obesity.