VCU news

By Lorraine Cichowski and Sarah Spiegel

RICHMOND, Va. – Researchers at Virginia Commonwealth University have identified an enzyme that appears to activate the new immunosuppressant drug, FTY720, which prevents rejection of transplanted organs without the toxic side effects of older drugs.

In findings, published this month in the journal FEBS Letters, the VCU researchers discovered how FTY720 is converted to its active form in the body’s cells to fight transplant rejection. 

FTY720 has been getting a lot of attention recently. The potent drug, which is being developed by Novartis, is derived from myriocin, a compound isolated from a fungus used in Chinese herbal medicine as an anti-aging agent. Clinical trials have demonstrated that FTY720 is successful in preventing rejection of kidney transplants in patients without causing the gastrointestinal toxicity common with other immunosuppressive drugs. Rejection, infection and drug toxicity are the most common problems suffered by transplant patients. In addition, laboratory animal tests have indicated FTY720 is effective against a variety of autoimmune disorders, including type I diabetes, lupus, arthritis and an animal form of multiple sclerosis.

Although researchers still are searching for all the answers about how FTY720 works, they do know that FTY720 is activated by the phosphorylation process, which describes a reaction in the body by which enzymes add a phosphate group to an inactive form of a drug, making it active.

“We know the phenomena. This is an important first step in understanding the mechanism of FTY720,” said Dr. Sarah Spiegel, chair of biochemistry and the lead author on the article. “We’re trying to understand how FTY720 is phosphorylated within the human cells and how it prevents transplant rejections and immune responses.”

Spiegel and her VCU team searched for the enzyme responsible for the phosphorylation of FTY720, noting that FTY720 is similar to the compound, sphingosine, whose phosphorylation is the major focus of the Spiegel lab. Spiegel’s team was the first several years ago to clone and characterize two enzymes known as sphingosine kinases -- SphK1 and SphK2 -- which phosphorylate sphingosine and which are very important in determining whether cells survive or die. In this study, supported by grants from the National Institutes of Health, they isolated these enzymes from human kidney cells and showed that SphK2 was 15 times more effective than SphK1 in converting FTY720 to a bioactive form. 

Spiegel said understanding how FTY720 works could help researchers design other novel, less-toxic immunosuppressive drugs. 

Spiegel, who is internationally recognized for her work on cell growth and death and immune responses, recently was honored by the NIH with a special long-term grant, valued at $2.1 million, to continue her research on sphingosine phosphate without having to apply for a grant extension. The highly selective “Method to Extend Research in Time” (MERIT) award is given to investigators who have demonstrated superior competence and productivity during previous research projects.