Drug slows AIDS

By MELANIE LUTZ
Collegian Science Writer

Penn State researchers have determined how a new class of AIDS drugs slows down a chemical reaction that is necessary for a strain of the virus to survive. The strain, HIV-1, is believed to be one of the strains that causes AIDS.

Kenneth A. Johnson, Paul Berg professor of biochemistry, said this discovery may lead to the formation of a more powerful and less toxic drug that can be used to treat AIDS. Their research, which was funded by the National Institutes of Health, will be published today in the journal Science.

Johnson said one of the drugs his team tested, Nevirapine, is being used in clinical trials. He said Rebecca Spence (graduate-chemistry), a student who works in his lab, has found that this new class of drugs slows down the virus' process of producing human genetic material, or DNA. This process is necessary for the virus to survive.

Spence is in San Francisco and could not be reached for comment.

HIV survives by transforming its genetic material, or RNA, into DNA, Johnson said. It does this by a replication process that is carried out by an enzyme of the virus. This enzyme is called reverse transcriptase.

This enzyme inserts its genetic code into the new DNA by using its own RNA, he said.

"It uses the RNA as a template for copying the chemical building blocks of DNA," Johnson said. Those chemical building blocks are nucleoside compounds found within the human cell.

A chemical reaction occurs and a new piece is added to the DNA strand. One piece, or base, of the DNA strand is built at a time. Johnson said once the DNA has been derived from the virus, it can be inserted into the DNA of a human cell and reproduce.

One problem researchers face when they study drugs used to treat AIDS is that the reverse transcriptase enzyme makes a lot of mistakes when it produces DNA, Johnson said. This means that about a billion different forms of the virus exist in a person who has AIDS. He said that trying to find a drug that works is like trying to hit a moving target.

Drugs currently used to fight HIV, such as AZT and ddC, lock on to a site on the reverse transcriptase enzyme where the nucleoside compounds normally attach and slow down the formation of the DNA, he said. They are just like the normal bases that will be incorporated into the DNA, he said, but they prevent further growth of the DNA strand.

This new class of drugs works differently. It binds at a different site -- a non-nucleoside site -- and slows down the chemical reaction that allows the next piece of DNA to grow. Johnson said it slows down the chemical reaction by a factor of 1,000 or more.

One problem with the nucleoside mimics, such as AZT, is that they are very toxic and kill mitochondria, which are necessary for the body to convert energy to food. The non-nucleoside drugs are very specific, so they do not have the same toxic effect, he said.

"We discovered something that we hadn't suspected," Johnson said. It may be possible to form a new and better inhibitor by fusing the nucleoside mimics with the non-nucleoside drugs, he said.