GOLD NANOPARTICLES: Researchers are studying whether substituting ammonium salt molecules with gold nanoparticles can create a compound that blocks HIV from infecting receptor proteins without harmful side effects. Image: Courtesy of North Carolina State University
Researchers believe that gold nanoparticles may breathe new life into once-promising drug candidates, in particular a compound designed to stop the spread of HIV (human immunodeficiency virus) that was shelved because of side effects. The compound—TAK-779—was first proposed by researchers in 1996 and proved effective at blocking the virus from infiltrating body's immune system. But it was scuttled by 2005, because recipients suffered severe irritation at injection sites and oral doses were ineffective.
Researchers have known for years that ammonium salt molecules in the compound triggered the bad reaction. But they could not find a benign replacement able to perform its function of binding the drug to T cells, white blood cells that fight infection including HIV.
Given TAK-779's success, however, Christian Melander, an assistant professor of chemistry at North Carolina State University in Raleigh, says scientists continued to search for a substitute, which they may finally have found.
Melander and colleagues David Margolis, a professor of infectious disease at the University of North Carolina at Chapel Hill, and Daniel Feldheim, an associate professor of analytical and materials chemistry at the University of Colorado at Boulder, reported online in the Journal of the American Chemical Society that gold nanoparticles may be the answer.
Scientists have already established that microscopic particles—including gold and silver—can help ferry chemical compounds from one place to another in lab tests. Massachusetts Institute of Technology (M.I.T.) engineers since 2004 have been studying the potential of gold nanoparticles (coated with alternating bands of two different kinds of molecules) in particular to penetrate the protective membranes around cells without damaging them.
But, whereas the M.I.T. scientists are using nanoparticles simply as an agent to assist drug delivery, Melander and his team want nanoparticles to also be an integral part of the drug itself. Melander says the key was to determine whether gold nanoparticles would, like the ammonium salt, latch onto receptors (protein molecules embedded in a cell's membrane) on the outside of T cells to shield them from HIV.
"It seemed you could take a particle and decorate it with something that would bind to the receptor to block it," he says. "Gold is nontoxic, and there's a great body of literature that shows you how to put a molecule on a gold particle."
Researchers found during lab tests that attaching 12 molecules of TAK-779—modified to exclude ammonium salt molecules—to one gold nanoparticle restored the drug's ability to prevent HIV infection. "This was a proof of concept that this will work," says Melander, who began the project two years ago.
The size of the gold particles—two nanometers (two billionths of a meter) in diameter—is comparable to that of the HIV proteins they are trying to block. This should make them well suited to stop viral proteins from coming in contact with key receptors, says Joseph Wedekind, an associate professor of biochemistry and biophysics in the University of Rochester School of Medicine and Dentistry.
The problem is that HIV targets different receptors on T-cells—and researchers only tested their compound on one of them. Another potential hitch is HIV's ability to mutate, and thereby become resistant to treatments over time, Melander says.
He notes that the next step will be to do a long-term study on whether HIV could change, eventually rendering the new compound impotent. Melander and his colleagues are also probing whether gold nanoparticles can be used to deliver an anti-HIV medicine directly to the human brain, where HIV is known to hide, replicate and mutate. "A lot of drugs can't get into the brain," he says, "even though the virus can."