By Sean Henahan, Access Excellence

WASHINGTON- The key discovery of the three dimensional structure of a key enzyme in the human immunodeficiency virus should open the door to a whole new area of AIDS research.

The enzyme, HIV integrase, is essential for HIV replication, as it is responsible for inserting the viral DNA into the DNA of the host. This enzyme is present only in the virus, not in mammalian cells. However, until now, no one knew what the enzyme looked like, or how it accomplished its task.

Researchers have been trying to define the crystalline structure of this enzyme for many years. However, they have been impeded by the fact that the protein is insoluble. To get around this, researchers at the National Institute of Diabetes and Digestive and Kidney Diseases created point mutations differing from the original by a mere single amino acid, substituting hydrophilic components for the original hydrophobic components.

The research team ultimately succeeded in finding one that was soluble which could then be crystallized. Using X-ray crystallography, the researchers were able to determine the three-dimensional structure of the core domain of a critical active region of HIV integrase.

The clarification of the structure of HIV integrase is bound to lead to innovations in anti-AIDS drug design. Knowing the shape of HIV integrase will allow drug developers to look for specific compounds to block the activity of the enzyme.

In a related research project, investigators have reported a discovery which helps explain how HIV integrase targets the host cell. It appears that a human protein found in many tissues including white blood cells, Ini1, binds tightly to HIV integrase in vitro and facilitates its DNA-joining activity. This could explain how HIV integrase binds to specific areas of the host cell genome.

Taken together, the two findings may lead to a practical way of blocking activity of this crucial enzyme, disrupting the HIV replication cycle by inhibiting HIV integrase activity and blocking the binding of Ini1.

Many of the therapies now used to treat AIDS, such as zidovudine (AZT), are targeted at another HIV enzyme, reverse transcriptase. A new class of drugs, the protease inhibitors, were specifically designed to inhibit another HIV enzyme, protease. However, mutant forms of HIV resistant to both these classes of drugs have already been observed.

The three dimensional structure of all three enzymes has now been elucidated, opening the way towards new drug development strategies. The hope is that a three-pronged approach could inhibit HIV replication enough to overcome the viruses rapid mutation rate, stopping it spread into other cells.

For extensive detail and discussion on this research see: Dyda et al. Science, v.266, 12/23/94, pp.1981-86. Also, Goff et al., same issue of Science, pp. 2002-2006, and discussion, pp 1946.

Transmitted: 94-12-29 20:41:34 EST

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