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Pitt researchers find candidates for new HIV drugs
Date:10/13/2009

PITTSBURGH, Oct. 13 While studying an HIV protein that plays an essential role in AIDS progression, researchers at the University of Pittsburgh School of Medicine have discovered compounds that show promise as novel treatments for the disease.

HIV drug discovery efforts have met with little success in finding compounds that interact with an important HIV virulence factor, called Nef, because it lacks biochemical activity that can be directly measured, explained Thomas E. Smithgall, Ph.D., William S. McEllroy Professor and Chair, Department of Microbiology and Molecular Genetics, and senior author of the paper, which was published last week in the early, online version of ACS Chemical Biology.

To get around that problem, Dr. Smithgall's team developed an assay to measure Nef function indirectly by coupling it to another protein, called Hck, which Nef activates in HIV-infected cells. Because Hck activity can be easily measured, the investigators were able to use it as a reporter for Nef activity in an automated high-throughput screening process. In collaboration with the University of Pittsburgh Drug Discovery Institute, they screened a library of 10,000 chemical compounds against the coupled proteins to see which ones influenced Nef-induced activation of Hck.

After further testing, they confirmed that three compounds inhibited the activity of the Nef-Hck complex and, more importantly, all of them also interfered with HIV replication. One compound was so effective that it suppressed HIV replication to undetectable levels in cell culture experiments.

"So we now have a way to rapidly and efficiently screen for inhibitors of Nef signaling through Hck," Dr. Smithgall said. "But the surprise was that some of those inhibitors also showed strong antiviral activity in cell culture models."

There is evidence that people infected with HIV variants that have mutations in the Nef gene take substantially longer to develop
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Contact: Anita Srikameswaran
SrikamAV@upmc.edu
412-578-9193
University of Pittsburgh Schools of the Health Sciences
Source:Eurekalert

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