Honing new weapon to counter HIV.

By teasing apart how a promising class of anti-AIDS drugs hinders the disease, researchers may have found a way to make the drugs more effective.

"The idea behind this analysis is important," says Stephen Hughes, an AIDS researcher at the National Cancer Institute in Frederick, Md. "We don't understand enough about HIV replication," he says of a new study conducted by biochemists Kenneth A. Johnson and Rebecca A. Spence of Pennsylvania State University in University Park and their colleagues.

HIV, the AIDS virus, enters human cells equipped with its own RNA, a template for making DNA. The virus manufactures DNA from this RNA using an enzyme called reverse transcriptase. It then inserts its DNA into that of the host cells, converting them into HIV factories.

AIDS drugs such as AZT and ddC trick the machinery of reverse transcriptase. They bind to a cleft on the enzyme that normally locks onto a nucleoside, one of the building blocks of DNA.

Unfortunately, these nucleoside-mimicking drugs can lead to serious side effects in patients. What's more, HIV mutates, churning out forms of reverse transcriptase that evade the drugs.

A new kind of medication now in clinical trials blocks reverse transcriptase by attaching not at its nucleoside binding site, but in a different spot. These so-called non-nucleoside inhibitors, including Nevirapine, cause fewer side effects than AZT because they're more specific.

The Penn State group halted early stages of DNA reactions in order to unravel the mechanism of three of these inhibitors. They found that the drugs don't stop the enzyme from binding to its target nucleoside.

Instead, they report in the Feb. 17 Science, the drugs appear to make the enzyme latch onto the nucleoside in a skewed position, hampering the chemical reaction by which the nucleoside attaches to other molecules. Indeed, the inhibitor makes the enzyme bind the nucleoside more tightly.

This supports a new strategy, Johnson says: Join the inhibitor and AZT or a related drug in a single molecule.

"This could give you something with a very high degree of specificity, lower toxicity, and it might be very effective," he says. By acting at two sites, such a drug might also stymie HIV's attempts to evolve a resistant form of reverse transcriptase, he adds.

The problem tackled by the Penn State team involves "horribly difficult analysis," Hughes notes. But "if [the analysis] is right, it's interesting and important."