The research will be presented at the 223rd national meeting of the American Chemical Society, April 7-11 in Orlando.
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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 it’s 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 Stukenberg of the University of Virginia Department of Biochemistry and Molecular Genetics.
Wang is a graduate student at Virginia Tech, and Hart earned his Ph.D. with Etzkorn at the University of Virginia (U.Va.).Other co-authors are Matt Mason at Virginia Tech and David Shonka and John Goodell at U.Va.
"(E)- and (Z)-Alkene Phospho-Ser-Pro substrate analogs for Pin-1, a phosphorylation-dependent peptidyl-prolyl-isomerase" (Orgn 376) will be presented at the Orlando ACS meeting on Wednesday, April 10, at 3:40 p.m. in Convention Center room 315A level 3.
Contact Dr. Etzkorn at 540-231-2235 or fetzkorn@vt.edu
There is a more detailed illustration of the trans, cis chemistry and a more detailed explanation at www.chem.vt.edu/chem-dept/etzkorn/homepage.htm
PR CONTACT: Susan Trulove (540) 231-5646 STrulove@vt.edu