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"What was different about what Randy did," says Deshaies, "is that the target was not defined at the outset of the screen. The 'target' was an entire system—a large group of proteins." That left open the possibility that compounds King identified blocked protein degradation at any of a number of steps. It was up to Verma and Deshaies to determine which one.
They analyzed King's compounds further using purified proteasomes and ubiquitin-tagged proteins. Verma and Deshaies systematically narrowed down the possible steps of the protein death march that the inhibitors were blocking. Their first experiments eliminated the two most obvious enzymatic possibilities: removal of the ubiquitin chain and degradation in the core of the proteasome.
The final answer was a surprise. Verma discovered that the inhibitors coated the ubiquitin chain, rendering it unrecognizable to the proteasome's ubiquitin receptors, thereby halting protein destruction before it could even begin.
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In this artist's conception, by medical illustrator Graham Johnson, a proteasome degrades a protein.
 View Illustration
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Small molecule inhibitors rarely work that way, she notes. Most, like bortezomib, clog the tight spaces at the reactive cores of enzymes. But a small molecule disrupting the broad surface contacts between proteins is like the fairy-tale pea poking the princess through a stack of mattresses.
Deshaies cautions that the compounds (which they named ubistatins) are still unsuitable as drugs. In fact, some of their chemical properties suggest that they may never enter the pharmaceutical pipeline. Instead, he says, "our research offers a proof in principle that the ubiquitin chain-receptor interaction is an Achilles' heel of the ubiquitin-proteasome system that is potentially inhibitable by small molecules." With that established, he says, pharmaceutical researchers might be able to accurately measure the binding of purified ubiquitin chains and ubiquitin chain receptor and then "screen a library of half a million compounds to find one that inhibits that binding."
Such a compound could treat diseases besides cancer, he says. Proteasomes play a key role in regulating inflammation, and proteasome inhibitors might have potential in treating inflammatory conditions, such as rheumatoid arthritis, or as anti-tissue rejection drugs for transplant patients. 
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