AIDS: building a better inhibitor.

AIDS: Building a better inhibitor

Pharmaceutical chemists have developed a compound that, in vitro, deactivates an enzyme vital to the maturation and function of the AIDS virus (HIV). The compound's novel structure may allow it to last longer in the body than other potential inhibitors of this enzyme.

Several research groups have been investigating chemicals to disrupt the activity of the AIDS virus by inhibiting one of its key enzymes, HIV protease. However, most of the more promising candidate inhibitors closely resemble peptides -- compounds that may be broken down by digestive enzymes long before they can effectively disarm HIV. In hopes of developing longer-lasting antiviral drugs, scientists have begun investigating chemicals tailored to match the structural geometry of the target site (SN: 6/23/90, p.390).

John Erickson and his colleagues at Abbott Laboratories in North Chicago had strong indications that unlike other human proteases, the HIV enzyme has a two-fold symmetry -- the left half of its "active site" is virtually a replica of its right half. The fact that peptides lack a two-fold symmetry suggested that some other type of compound might inhibit HIV protease as effectively. Identifuing a bilaterally symmetric compound that roughly matches the shape of the enzyme's active core region, Erickson's team subtly modified its structure until the target enzyme's amino acid side chains could bind this new compound in a tight embrace.

In the Aug. 3 SCIENCE, the Abbott scietists report that this compound -- A-74704 -- slowed HIV protease activity and infection of human T-lymphocytes by the AIDS virus in vitro. The new compound is highly selective, they note. It bound to HIV protease in vitro 10,000 times more effectively than to several other human proteases.

In analyzing the crystal structure of the inhibitor-bound enzyme, the team found that a water molecule within the enzyme links atoms on the protease's surface to those on the inhibitor. Erickson speculates that drugs designed to push aside the water molecule and mimic its linking ability may bind protease even more strongly. His group is now developing such drugs, he says.