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Chemists explore the shape of the key that signals cell division in cancer cells

(Blacksburg, Va., April 10, 2002) -- Virginia Tech chemistry professor Felicia Etzkorn and her students are designing small molecules to mimic peptides in order to determine which form is critical to initiating cell division in cancer cells. The ultimate goal is to be able to design drugs to stop the cancer cell cycle.

The research will be presented at the 223rd national meeting of the American Chemical Society, April 7-11 in Orlando.

Etzkorn explains, "We are doing rational drug design, targeting the cell-cycle-regulating enzyme, Pin1, with an eye towards anticancer activity."

Pin1 is important because it is the enzyme that regulates the protein Cdc25, which initiates mitosis or cell division. Pin1 is the gatekeeper to cell division. Without Pin1, the cell enters programmed cell death -- which is a good if its a cancer cell.

"We are designing small molecules that are peptide mimics. In this case, we have synthesized a peptide locked into two shapes, or conformations, called isomers. One of these isomers may inhibit the action of Pin1, but they have not been biologically tested yet," Etzkorn emphasizes.

Pin1 works by changing a peptide bond within Cdc25 from the trans shape to the cis shape and back. It is a simple change -- the swing of an arm one way or another, but over the length of many amino acids in a protein it is a large conformation change. "We don't know whether the trans shape or the cis shape signals Cdc25 to begin mitosis -- which is the active shape," says Etzkorn.

Graduate students Xiaodong (Jane) Wang and Scott Hart are the lead authors of the paper to be presented at ACS. "They have done a beautiful job of asymmetric synthesis of these molecules, providing high yields so we will have enough to test them biologically," says Etzkorn.

The next step is to include the mimics in a longer peptide, which will be tested biologically in Etzkorn's lab with Pin1 supplied by collaborator Todd
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Contact: Felicia Etzkorn
fetzkorn@vt.edu
540-231-2235
Virginia Tech
10-Apr-2002


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