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Researchers, Led by Chi-Huey Wong, Develop Protease Inhibitors Against HIV

A group of TSRI scientists, led by Chi-Huey Wong, Ph.D., has developed a new protease inhibitor that is effective against mutating strains of the AIDS virus that are resistant to current drugs. The work was published recently in The Journal of the American Chemical Society.

Most therapies against the HIV virus disable it by latching onto an enzyme that the virus needs to multiply. However, the virus' ability to quickly mutate renders the inhibitors ineffective within weeks. The most successful treatment to date attempts to overwhelm HIV with two or three of these drugs in a combination therapy, but even this approach eventually becomes ineffective.

But, Wong now thinks he knows how HIV adapts readily to these treatments. Over time HIV proteases apparently change structure so that the inhibitors can no longer bind tightly. He commented, "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."

The researchers looked at the corresponding binding site on HIV protease inhibitors and discovered that most of them have large chemical structures that interact with the constrict-ed areas in drug-resistant proteases. By redesigning the drugs, they have given them a smaller chemical group at the critical binding site that increased their effectiveness against both HIV protease and its drug-resistant mutants. "More important," 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."

The same chemical also may become the first treatment for feline AIDS, a major threat to the world's cat population.