CHEMICAL & ENGINEERING
NEWS OF THE WEEK NÔVEMBER
18,
2002 EDITËDBY JANICE LONG & STEPHEN TRZASKA
SCIENCE
DESIGNER KEYS FOR MUTATED LOCKS Vitamin D analogs bind with mutated receptors in genetic disease approach
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AY YOUR BODY PRODUCES A
mutant protein that can't bind to and therefore cannot process a vital nutrient. Some might say the best answer is gene therapy—alteringyour cells' DNA to produce the correct protein. But chemistry professor John T. Koh's group at the University of Delaware is approaching the problem from a different angle. Their strategy: Change the nutrient to fit the mutant. For example, a few people suffer from a disease known as vitamin D resistant rickets (VDRR). Because they generate mutated vitamin D receptors, their bodies cannot make use ofvitamin D and their bones soften severely Now Koh, graduate student Steve L. Swann, and their colleagues have synthesized variants of vitamin D. These analogs are much better complements to one mutant vitamin D receptor than is the natural compound \J. Am. Chem. Soc, 124, 13795 (2002); Org. Lett., 4,3863 (2002)]. In addition to Koh, a number of researchers, including University of California, Berkeley associate chemistry professor Kevan M. Shokat and David R. Corey, associate professor in pharmacology and biochemistry at the University of Texas Southwestern Medical Center, have paved the way for this approach with their work on ligand receptor engineering. Koh's group has taken things a step further by targeting a real HTTP://PUBS.ACS.ORG/CEN
clinical problem. The structure of the normal vitamin D receptor, which is part of a broad superfamily known as nuclear hormone receptors, is known from cristallographie data. Numerous different mutants can lead to VDRR, but Koh's group identified one in particular, in which an arginine located in the binding pocket is mutated to leucine. The mutated receptor binds vitamin D with only a thousandth the efficiency of the normal receptor. W i t h the help of computer modeling, they identified a slew of vitamin D analogs that potentially could bind to the mutant. They synthesized the most promising compounds and tested them in cell lines with the mutant receptor. The researchers discovered that some of the analogs activated the mutant receptor 500 times as well as normal vitamin D. "This was a smart experiment, one of the most clever applications of chemical biology that I have seen," Corey says. In fact, Koh's group has also designed a compound that restores activity to a mutant form of the thyroid hormone receptor, which causes the genetic disease RTH (resistance to thyroid hormone). The researchers are now working with a physician with an eye toward eventual human testing
MUTANT FIT Normal vitamin D (orange) binds extremely poorly to a mutant vitamin D receptor, but a specially designed vitamin D analog (green) does the job well.
of the thyroid hormone analogs. This strategy should work for other genetic diseases in which receptors bind very specifically "Some are really lock and key," says RobertJ. Fletterick, professor of biochemistry and biophysics and cellular and molecular pharmacology at UC San Francisco. "Change the lock by mutation and then just change the key" However, other receptors are not quite so discriminating. "It's relatively easy to identify effective ligands for mutant nuclear hormone receptors because of their hydrophobic pockets," Corey says. "It will be more challenging to apply the approach to other proteins." Nevertheless, Corey says, "this approach is clearly one that should be taken seriously"—ELIZABETH WILSON C&EN
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