LA JOLLA, CA June 13, 2012 Scientists at The Scripps Research Institute have used a powerful new chemical-screening method to find compounds that inhibit the activity of human immunodeficiency virus (HIV), the virus that causes AIDS. Unlike existing anti-HIV drugs, the compounds bind to a protein called "nucelocapsid," which is unlikely to mutate into drug-resistant forms.
"Most of the nucleocapsid-inhibiting compounds that have been identified to date are very toxic, but our screening method identified inhibitors that are less toxic and thus more likely to lead to useful drugs," said Scripps Research Associate Professor Bruce Torbett. Torbett is the senior author of the new report, which appears in the June 14, 2012 print issue of the Journal of Medicinal Chemistry.
HIV's nucleocapsid protein binds to the viral genome to package and protect it, and plays a key role in the assembly of new virus copies, as well as in the reverse transcription of the viral genome into DNA. It has long been a target of HIV drug developers because it grabs hold of the viral genome using protein structuresknown as zinc knucklesthat can't change much without losing their functionality. It thus is thought to have little room to mutate into drug-resistant forms, in contrast with other HIV proteins.
Screening Out Toxicity
However, despite almost two decades of research, there are still no FDA-approved drugs that target HIV's nucleocapsid protein and its zinc knuckle structures. One reason is that similar structures exist on many healthy cellular proteins; thus compounds that target them are apt to have unwanted side effects. "When researchers have targeted these nucleocapsid zinc knuckles in the past, they've usually ended up producing toxicity," Torbett said.
To increase the chances of finding safe compounds, Torbett and his colleaguespostdoctoral researcher Sebastian Breuer, the study's first author, and Max Chang and
|Contact: Mika Ono|
Scripps Research Institute