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University of Pittsburgh Team Finds "Achilles Heel" of Key HIV Replication Protein

January 28, 2013

University of Pittsburgh School of Medicine researchers report they have developed a way to track -- and perhaps block -- the activity of Nef, an HIV protein that is critical to HIV replication. According to researcher Thomas Smithgall, Ph.D., the team reasoned it might be possible to stop HIV replication by preventing Nef's "usual interactions with other proteins."

The researchers linked Nef to Hck -- an enzyme activated in HIV-infected cells -- and screened close to 250,000 compounds for a compound that would block Nef's role in replication. The automated screening procedure identified a promising compound, B9, which interrupts Nef's role in HIV replication by preventing two Nef molecules from forming "dimers," an essential step in the HIV replication process.

The team believes their discovery of the point where B9 binds to Nef could lead to the invention of new drugs that could prevent HIV from developing into AIDS. Smithgall says test-tube and cell culture experiments confirm this spot is an HIV "Achilles heel" that could be a target for drugs that stop the virus from replicating. The University of Pittsburgh Drug Discovery Institute is working to find a formula similar to B9 that can be tested with animals.

The full report, "Effector Kinase Coupling Enables High-Throughput Screens for Direct HIV-1 Nef Antagonists With Antiretroviral Activity," was published online in the journal Chemistry & Biology (2013; 20(1):82-91).

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