"Our robots wound up being powerless for tackling this particular problem," he says. "Ironically, it was an old-fashioned method that made this breakthrough possible."
The old-fashioned approach involved using a technology invented in 1950 to figure which peptide sequence among trillions of possible combinations IDE chops up most efficiently. Benjamin Turk, Ph.D., of Yale University School of Medicine, conducted this critical step. Then, a team of chemists led by Gregory Cuny, Ph.D., director of Medicinal Chemistry at the LDDN, generated a compound that contained the preferred peptide sequence, together with a special chemical group that binds to zinc. The resulting compound is called "Ii1" (IDE inhibitor 1).
Ii1 is about a million times more potent than any previous IDE inhibitors, but additional work will be needed to turn it into a drug suitable for therapeutic use, Dr. Leissring says. In a key step towards this goal, Dr. Leissring, together with Wei-Jen Tang, Ph.D., and other colleagues from the University of Chicago, solved the 3-dimensional crystal structure of Ii1 bound to IDE. This crystal structure will facilitate the development of inhibitors that are more stable in the body than Ii1 is predicted to be.
The structure of IDE is unlike other proteases, the researchers say. It is shaped like a hinged clamshell that opens and shuts, like the well-known video game protagonist, Pac-Man.
The researchers found from their crystal structure that the Ii1 peptide acts like a magnetic latch that holds the clamshell shut. "Think of a coin purse that uses a magnet at the top to
|Contact: Kevin Punsky|