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New Protease Inhibitor Could Thwart AIDS Resistance To Current Drugs

Researchers have developed a new protease inhibitor effective against mutating strains of the human AIDS virus that are resistant to current drugs, according to a just-released report in the peer-reviewed Journal of the American Chemical Society.

The paper will be published on the web on Feb. 4 and will be in the journal's Feb. 17 print edition. The American Chemical Society is the world's largest scientific society.

Most AIDS drugs disable the human immunodeficiency virus (HIV) by latching onto an enzyme, such as a protease, that the virus needs to multiply. However, HIV quickly mutates and becomes resistant to individual inhibitors within weeks.

The most successful treatment to date tries to overwhelm HIV with two or three of these drugs simultaneously in a so-called "combination therapy," but even this approach eventually loses effectiveness.

Researchers at The Scripps Research Institute in La Jolla, Calif. think they now know how HIV adapts so readily to the current treatments. Over time, HIV proteases apparently change structure so that the inhibitors can no longer bind tightly. "We have studied the mutation pattern of HIV protease from patients who take the existing drugs and found that the enzyme often rejects the drug by reducing the size of the drug binding site," says Scripps chemist Chi-Huey Wong, Ph.D.

The scientists then looked at the corresponding binding site on current HIV protease inhibitors and found that most of them have large chemical structures that interact with the constricted areas in drug-resistant proteases. So they redesigned the drugs, giving them a smaller chemical group at the critical binding site. In laboratory tests, the new class of inhibitors was effective against both HIV protease and its drug-resistant mutants. "More importantly," adds Wong, "no resistant mutants were detected in cell culture after one year the new drug may last longer as the chance for development of drug resistance is lower
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Contact: Nancy Blount
n_blount@acs.org
202-872-4440
American Chemical Society
3-Feb-1999


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