A random screening of several drugs by P&S researchers has found that three common antivirals can prevent sickling of red blood cells from patients with sickle cell disease, preserving their normal, doughnut shapes. The antivirals acyclovir, valacyclovir, and ganciclovir are usually prescribed to lessen the symptoms of chickenpox and herpes infections. Their efficacy in preserving the shape of red blood cells, however, could lead to new drugs for sickle cell anemia, a disease with few treatment options.
For the 70,000 Americans with the disease, sickled cells lead to clots in the liver, the lungs, the brain essentially all the organs of the body. "Over the years, the constant interference with the organs leads to organ failure; people lose splenic function and develop liver failure, or they can have strokes," says Dr. Robert DeBellis, associate clinical professor of medicine and lead author of the study. "If you can prevent sickling, you essentially stop what the disease is all about."
One way to prevent sickling is to prevent the polymerization of hemoglobin S the type of hemoglobin produced in sickle cell anemia instead of hemoglobin A. After hemoglobin S molecules release oxygen to the tissues, the molecules rapidly polymerize into long rods inside the cells. The rods force the red blood cells to take on a sickled shape.
Current therapies aim to boost the patient's production of fetal hemoglobin, because fetal hemoglobin also interferes with hemoglobin S polymerization. For the past five years, one such agent a cancer chemotherapy drug called hydroxyurea has been available, but concern over unknown consequences from its long-term use has led many patients to reject the treatment. Aside from a bone marrow transplant, nothing is able to stop the disease, and many patients succumb in their 40s and 50s. "No one neither doctor or patient is satisfied with the limitations on currently available treatments," Dr. DeBellis says.
With Dr. Bernard Erlanger, professor emeritus of microbiology, and staff associate Bi-Xing Chen, Dr. DeBellis originally tried to use small fragments of hemoglobin to break up the bundles of hemoglobin S and prevent sickling, but the strategy didn't work. They turned to a less rational approach.
"My early background was in industry, where you try things at random," Dr. Erlanger says, "so we took drugs off the shelf and did a screen. We selected acyclovir because Dr. DeBellis happened to have it in his office." Dr. DeBellis uses the antiviral drug with his cancer patients who get frequent viral infections because their immune systems are compromised.
"It was a purely random screening process, but we found that, in vitro, acyclovir prevented sickling of erythrocytes from sickle cell patients," Dr. Erlanger says.
The researchers then tried other antivirals that are structurally similar to acyclovir. Ganciclovir and valacyclovir also transformed sickled cells into normal-looking erythrocytes. Another structurally similar antiviral, penciclovir, did not. The findings were published in the September issue of Blood Cells, Molecules, and Diseases.
Dr. DeBellis is planning to test the antivirals in patients to see if the excruciatingly painful clotting crises that are caused by sickled cells can be prevented or stopped once they occur. The drug concentrations used in the sickling assays are probably not possible in patients, but the researchers say the antivirals should work at much lower concentrations because patients never experience a total lack of oxygen, as was the case in the assays.
Dr. Erlanger says they don't yet know how the drugs work but some clues may come from their almost identical structures. When the two-dimensional structures of each drug were compared, the ineffective antiviral, penciclovir, differed only in having a carbon atom in place of an oxygen present in the three effective drugs. "Modeling studies need to be done next," Dr. Erlanger says. "In two dimensions you see only a missing oxygen, but in three dimensions we may see something else going on. Based on the modeling, we might be able to design some better agents."