San Francisco Chronicle - Tuesday, July 9, 2002
Sabin Russell, Chronicle Medical Writer

At a packed session that surveyed potential new AIDS drugs, a top scientist at Merck Research Laboratories reported that a long-sought chemical known as an integrase inhibitor has knocked down an AIDS-like virus in monkeys and has been tested safely in human volunteers.

Integrase is one of three enzymes inside the AIDS virus that help it make copies of itself after it invades a human blood cell. The others are known as reverse transcriptase and protease. Every AIDS drug on the market today tries to block one of those two enzymes.

"This completes a triangle," said Dr. Warner Greene, director of UCSF's Gladstone Institute of Virology and Immunology. "It is very good news."

Meanwhile, researchers from Swiss pharmaceutical giant Hoffmann-La Roche and North Carolina partner Trimeris Inc. reported favorable results for another experimental drug known as T-20. The most advanced in a new category of drugs called fusion inhibitors, T-20 targets an entirely different part of the AIDS virus, working on the surface to block entry into blood cells.

T-20 performed very well in a pair of six-month studies that enrolled almost 1,000 patients who were failing older antiviral drugs. After 24 weeks, the amount of virus in the blood dropped below detectable levels in 37 percent of those getting the drug, compared with 16 percent of those on normal treatment. There were few side effects.

"Based on these results, I think it's not in any way premature to say that T-20 is likely to become a key component of a future optimized regimen both in the United States and in Europe," Dr. Jacob Lalezari, director of Quest Clinical Research and a former researcher at UCSF, told the Associated Press. Together, the T-20 and integrase reports are encouraging signs that a newer generation of AIDS drugs, perhaps better than the first, is progressing on the path from the laboratory to the clinic.

Greene is one of the leading scientists conducting basic research on the genetic blueprint of HIV, the virus that causes AIDS. Like mechanics picking apart a car to see how it works, scientists in Greene's lab have dissected the nine genes and 15 proteins of the AIDS virus and are learning their functions. Each is a potential target for new drugs or vaccines. While fusion inhibitors such as T-20 have been in development for a while, Merck's integrase drug is the first new class of AIDS medicines to be tested on humans in many years.

A DIFFICULT ENZYME

Enzymes are choice targets for drugs because they are easier to attack with simple chemicals than are other viral components. The trick is to understand how the enzyme works. But integrase proved frustrating.

Merck researcher Daria Hazuda, whose unit discovered the new integrase inhibitor, described in an interview how the potential new AIDS drug has been at least 10 years in the making.

Unlike the other enzymes, integrase proved a difficult nut to crack because it works in three steps. Most researchers around the country focused on the first two, but Hazuda's team worked the third.

"We just looked at it differently," she said.

On Monday, Hazuda said a candidate chemical that blocked this third step was tested in monkeys infected with an AIDS-like virus chosen because it is particularly deadly to the animals.

Within 10 days of taking the new drug, virus levels in the blood of 4 of 6 monkeys was so low it could not be detected. Levels of infection-fighting white blood cells rose after the therapy.

The new drug has been tested in about 70 humans, healthy volunteers who agreed to take it to test its safety, Hazuda said. So far, it has been safe. Tests in HIV-infected volunteers are next.

Because HIV enzymes have been such valuable targets for new drugs, there is an unusual degree of interest in the early phases of this trial. But there are at least 22 different new AIDS drug candidates undergoing clinical trials -- many of them aimed at new targets researchers have discovered in the AIDS virus. The furthest along of these new drugs is T-20.

WORKING ON THE SURFACE

Instead of blocking an enzyme like all other approved AIDS drugs, fusion inhibitors interfere with the process the AIDS virus uses to insert its genetic material into a blood cell. It works on the surface of the virus, rather than inside.

But T-20 is made from a short protein chain called a peptide and, as such, is a devilishly difficult and expensive drug to make. Another potential drawback: T-20 has to be injected, rather than taken in pill form.

While scientists in Barcelona were not surprised by the announcements about either drug, the reports were nevertheless welcome relief from the drumbeat of news about HIV's eventual ability to sidestep virtually every drug thrown against it.

That optimism was tempered by observations of Johns Hopkins University AIDS expert Dr. Robert Siliciano, who predicted Monday that the AIDS virus may be stopped from reproducing by good antiviral drugs, but it can never be purged from the body of those infected.

"The virus establishes a state of silent infection," he explained. "It is intrinsically incurable with antiretroviral drugs alone."

E-mail Sabin Russell at srussell@sfchronicle.com.
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