Studying an HIV protein that plays a key role in AIDS progression has helped University of Pittsburgh School of Medicine researchers discover compounds that show promise as novel treatments for the disease.
Study author Thomas E. Smithgall explained that 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.
To get around that problem, 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 researchers were able to use it as a reporter for Nef activity in an automated high-throughput screening process.
The researchers 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.
The researchers found that 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. But the surprise was that some of those inhibitors also showed strong antiviral activity in cell culture models," Smithgall said.
He said that there is evidence that people infected with HIV variants that have mutations in the Nef gene take substantially longer to develop disease symptoms or AIDS. In animal models, disrupting the production of Nef from the virus or its interaction with Hck also delays or prevents disease symptoms.
The study was published in the early, online version of ACS Chemical Biology.