CURRENT estimates suggest that half of the people living in North America and Europe will die from a blood clot in a vital organ such as the heart, the brain or a lung. Preventing clots is therefore an important goal, and two recent advances have brought that goal nearer.
Athan Kuliopulos, of the New England Medical Centre in Boston, and his colleagues have focused on cellular receptors. Body cells bristle with receptor molecules that react to chemical messages from elsewhere. If these receptors are blocked, the cell does not know what is happening in the outside world, and so does not react.
Many drugs work by blocking receptors. In particular, more than 50% of prescription drugs stick to a group of molecules known as G-protein-coupled receptors (GPCRs). There are more than 1,000 types of human GPCR. Two of them are responsible for deciding when platelets—the cellular fragments that create blood clots—should stick together to form such a clot. Blocking these two receptors should prevent clotting. Doing so, though, has proved an intractable problem.
Dr Kuliopulos decided that if he could not block them on the outside of the cell's external membrane (the traditional way of doing these things), he would, as it were, go through the back door and block them on the inside of the membrane. The trick was to get the blocking agent—a fragment of protein known as a peptide—across that membrane. He achieved this by attaching the peptide to a molecule made of the same stuff as cell membranes. The result was a combined molecule, called a pepducin, that partially dissolves in cell membranes, and thus can penetrate them.
The new agent will have to go through many years of testing before it can hope to become a drug. But Dr Kuliopulos says that experiments in mice and on human blood cells—described in this month's Nature Medicine—have shown that his pepducin blocks both of the relevant platelet GPCRs. It therefore has the hallmarks of a powerful anti-clotting agent.
Although there are many existing anti-coagulants, none is perfect. Pepducins may be able to help the 5-7% of patients who react adversely, or not at all, to existing ones. Blocking the receptors on the inside of the cell in this way also turns out to be a completely novel method of disabling GPCRs. So the researchers think that pepducins have potential as drugs affecting other GPCRs, and thus other diseases.
Preventing platelets from clotting is just one means of preventing blockages from forming inside blood vessels. Another is to stop those vessels becoming inflamed, and thus being susceptible to such blockage in the first place. In an article in the current issue of Stroke, John Hallenbeck, of America's National Institute of Neurological Disorders and Stroke, and his colleagues showed that they could vaccinate against the sort of inflammation that constricts blood vessels, thereby reducing the frequency and severity of strokes in experimental animals. They did this by interfering with a protein called E-selectin, which contributes to inflammation. By exposing rats to E-selectin, they were able to provoke an immune response to this protein. That meant that the rats produced antibodies against E-selectin when blood-vessel cells started to turn it out. The antibodies knocked out the protein and thus suppressed the inflammation.