San Francisco Chronicle (SF) - MONDAY, May 29, 1995 Edition: FINAL Section: News Page: A7 Word Count: 506
David Perlman, Chronicle Science Editor

Scientists at the University of California in San Francisco reported last week that with the aid of specialized computer programs, they have created a "designer" drug. In the laboratory, the drug prevents the AIDS virus from infecting new cells grown in lab cultures and from replicating inside cells that already have been infected.

Whether the new type of drug will act the same way in human immune system cells has not been established, the researchers said.

The promising new drug, however, appears to overcome one crucial defect in a relatively new class of other drugs that AIDS researchers had thought might prove a powerful way to attack infection by HIV, the virus that causes AIDS.

Those drugs, known as protease inhibitors, block a key enzyme inside the virus that is necessary for HIV to reproduce when it captures the genetic machinery of the cells it invades. When the drugs were first tested in humans, they appeared to work spectacularly, reducing the number of new viruses in HIV-infected patients and rapidly increasing the numbers of their immune system cells.

But only two months ago, makers of the protease inhibitors reported disturbing news: The AIDS virus quickly mutated to become resistant to one of the drugs. And when "cocktails" combining several protease inhibitors were brought into the battle against HIV, the wily virus mutated again and again to develop "cross-resistance" that weakened the drugs' power.

The virus also has shown an equally remarkable ability to develop resistance to other AIDS drugs, including AZT, the first anti-viral compound used in the campaign against the epidemic.

At the annual meeting of the American Society for Biochemistry and Molecular Biology at Moscone Center last week, Charles Craik of UCSF reported on his research team's attempt to prevent HIV from mutating to resist protease inhibitors.

Using computers to reveal the complex structure of the protease enzymes, Craik and his colleagues found a way to insert a defective gene into the virus -- a gene that produced a version of the viral protease, which in turn proved so defective that the virus could no longer use it to reproduce.

In the laboratory, the researchers then inserted the defective genes into the immune system cells of monkeys. And when HIV invaded the monkey cells to take over their genetic machinery, the virus produced its own defective protease that made it unable to reproduce and to infect other cells, Craik reported.

The genetic change in the viral DNA that produced the defective protease became what Craik's team calls a "trans-dominant inhibitor" -- a "designer drug" created from the defective protease. Craik believes that this new drug might make it unlikely that HIV could mutate in order to develop resistance to protease inhibitors or to other AIDS drugs of comparable size and structure.

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