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Blunting the Scissors

Although the cutting enzymes themselves proved maddeningly elusive, this model of Alzheimer’s offered an obvious strategy for attacking the disease: block the enzymes and prevent the plaques. Since 1992, many drug companies have been looking for “secretase inhibitors,” molecules that would block either gamma- or beta-secretase. One compound, a gamma-secretase inhibitor discovered at Bristol-Myers Squibb using mass screening techniques, entered early human trials in April 2000. “We’re on the verge now of either preventing amyloid deposits from building up, inhibiting the production of amyloid, or actually being able to reverse plaque deposition,” says Felsenstein, who leads Bristol-Myers Squibb’s amyloid program. Other pharmaceutical firms-including DuPont, Merck, Elan and Eli Lilly-are testing gamma-secretase inhibitors as well, but haven’t yet disclosed human trials.

But the drug-discovery process has been agonizingly slow. Just randomly sprinkling compounds on cells and measuring amyloid levels requires both time and luck to get a good hit. In fact, many drug companies ignored the secretases, since without the enzymes in hand, there’s no way to know how specifically a compound is targeting them-making toxic side effects largely unpredictable.

Finding beta-secretase changes everything. Now medicinal chemists can design molecules to fit precisely into the enzyme’s “active site.” In theory, such drugs should be exquisitely specific, avoiding the worst side effects. Citron says Amgen is very excited about that possibility. The company has figured out the three-dimensional structure of the beta enzyme and is fashioning molecules to block its activity.

Industry insiders say that Amgen has lots of competition, though companies are more open about their gamma programs. GlaxoSmithKline of London, another company to have isolated the beta-secretase gene, is one player officially working to inhibit it. And Dublin, Ireland-based Elan and its partner in Peapack, NJ, Pharmacia, have also launched a major push. “Both of us view beta-secretase as a terrific target,” says Dale Schenk, vice president of discovery research for Elan. “I don’t think it’s going to be terribly long before the field has clinical candidates.”

Schenk’s optimism is based, in part, on an obvious precedent: AIDS. That’s because beta-secretase is a protease, or protein-cutting enzyme, in the same class as the HIV protease, which proved to be a great drug target. Once the HIV-protease structure was discovered in 1989, it took less than three years to get “protease inhibitors” into the clinic. These drugs have changed AIDS from a death sentence into a usually manageable condition. “Pharmaceutical companies like sure things,” says University of South Florida Alzheimer’s researcher Huntington Potter. Blocking enzymes “is something they can do easily and be sure that they have something fairly successful at the end.”

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Tagged: Biomedicine

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