HIV ‘Achilles heel’ could be new drug target

U. PITTSBURGH (US) — By targeting a vulnerable spot in a key HIV protein, researchers believe they may be able to stop the virus from replicating and possibly keep it from progressing to full-blown AIDS.

Previous research demonstrated that a small HIV protein called Nef interacts with many other proteins in infected cells to help the virus multiply and hide from the immune system.

For the new study, published online in the journal Chemistry and Biology, researchers developed a way to track Nef activity in high-throughput drug screening protocols by linking it to an enzyme called Hck, which is activated by Nef in HIV-infected cells.


“We reasoned that agents that prevent Nef from its usual interactions with other proteins might be able to stop HIV from replicating and infecting other cells,” says Thomas E. Smithgall, professor and chair in the Department of Microbiology and Molecular Genetics at the University of Pittsburgh.

“For this study, we devised an automated screening procedure and tested nearly 250,000 compounds to find ones that could block Nef activity.”

One of the compounds they discovered, called B9, seemed particularly potent at blocking Nef. In follow-up experiments, the research team examined how B9 accomplished this and found that it could prevent two Nef molecules from interacting to form dimers as effectively as a mutation in a critical area of the protein surface. The inability of Nef to dimerize consequently impairs its function in the viral replication process.

“This pocket where B9 binds to Nef and where Nef forms a dimer indicates it’s a hot spot, or Achilles heel, that could represent a new target for HIV drugs,” Smithgall says. “Our test tube and cell culture experiments show that blocking this site brings HIV replication to a halt.”

The team is working with medicinal chemists at the University of Pittsburgh Drug Discovery Institute (DDI) to find analogs of B9 that have therapeutic potential, and they plan to assess them in animal models of HIV/AIDS.

Researchers from the University of Virginia contributed to the study, which was funded by the National Institutes of Health.

Source: University of Pittsburgh

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