The Wall Street Journal - January 28, 2000
Michael Waldholz, Staff Reporter of The Wall Street Journal

The Merck scientists are reporting in the journal Science Friday that they have found two experimental compounds that in laboratory tests were able to obstruct the activity of an enzyme called integrase that plays a critical role when the AIDS virus infects cells. In an interview, a Merck spokesman noted that the compounds themselves aren't useful as human medicines and that Merck is still a long way from turning the research into drugs. But it opens an avenue of exploration in the company's intensive search for AIDS treatments.

"We're reporting a very technical piece of biochemistry," said Larry Hirsch, vice president for public affairs at Merck. Dr. Hirsch said the compounds that blocked the action of the integrase enzyme don't have the characteristics required for human drugs.

Study May Renew Hope

Still, the report is expected to renew hope that drug makers will be able to create a new class of drugs against HIV, the virus that causes AIDS. At present, the principal medicines that make up the multidrug cocktails against HIV work by targeting other enzymes inside the AIDS virus. Merck's Crixivan drug and others like it, for instance, disrupt the action of the protease enzyme, while Glaxo Wellcome PLC's AZT and 3TC, and drugs that work like them, block an enzyme called reverse transcriptase.

For years, ever since scientists first identified the integrase enzyme inside HIV about 12 years ago, drug makers have been unsuccessful in coming up with chemicals that shut down the enzyme's action. While researchers seeking ways to disable HIV were quickly able to come up with experimental agents to block the protease and reverse transcriptase enzymes -- developments that eventually led them to usable medicines -- the Merck report appears to be the first time biochemists have found a family of molecules that may serve as a basis for an integrase-blocking drug.

The protease and reverse transcriptase enzymes help HIV reproduce itself into swarms of offspring after the virus has infected the nucleus of a human white blood cell. But integrase has been seen as an especially attractive enzyme to attack because it actually provides the crucial step in which the virus enters, or integrates, its genetic material into the genetic material of the target human white cell. Scientists have long believed that if they could produce a drug that somehow impedes integrase they would be able to stop the virus before it can invade the cell's nucleus, clearly a potentially promising way to thwart infection. The AIDS virus's ability to integrate its DNA into human cells helps it evade the immune system and is one reason it is so difficult to eradicate from the body.

But over the years, drug makers like Merck have been unable to create a lab assay in which they could test thousands of chemicals to see if any can block integrase. That is because in a test-tube setting integrase seems to behave differently than when it is in the virus or in the human body. One important advance by Merck appears to be the creation of a system to test potential integrase blockers.

In the new report, Daria Hazuda, a Merck biochemist, and her colleagues said they eventually screened about 250,000 chemicals until they found two that were able to keep integrase from carrying out its job. The compounds, part of a chemical family known as diketo acid inhibitors, were shown in test-tube studies to keep HIV's genetic material from combining with the genetic material of white cells.

Compounds Help Block Replication

The report also suggests the compounds were especially potent in blocking HIV replication when compared with similar tests of existing drugs. The researchers reported that there was some reason to believe the virus might not be able to generate resistance against such an integrase-blocking drug as quickly as it presently does against existing drugs.

The findings will probably trigger a race among competing pharmaceuticals companies to find similar compounds. Drug makers are seeking other HIV medicines for several reasons. Although the cocktail of medicines has revolutionized AIDS treatment for many people since they were introduced four years ago, a portion of patients eventually become resistant to one or more of the drugs. In addition, the drugs all produce side effects that make taking the drugs difficult. Scientists hope that by adding a new drug to the cocktail, one that attacks the virus differently from the medicines now used, they may be able to prolong the therapy's effectiveness.

Dr. Hazuda is scheduled to present her research Sunday in San Francisco to a large AIDS-research meeting where she is likely to get a great deal of attention from her scientific peers and the media.

Write to Michael Waldholz at michael.waldholz@dowjones.com1
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