Call them the Virus Busters. Drexel University scientists Irwin Chaiken and Cameron F. Abrams have created a designer molecule to trick HIV into self-destructing, providing promising leads not only on ways to fight the disease but also to prevent initial infection.
“We’re learning that the virus can be defeated in a very specific way,” says Chaiken, a professor of biochemistry and molecular biology in the College of Medicine. He is collaborating on the project with Abrams, a professor of chemical and biological engineering in the College of Engineering.
Chaiken’s lab has already created two other novel classes of compounds to inactivate the human immunodeficiency virus (HIV), which kills more than 2 million people every year. His work with Abrams has led to a new, uniquely interesting class known as DAVEI, which stands for dual-action virolytic entry inhibitor.
In conversations with Chaiken a few years ago, Abrams shared his hypothesis that the virus is under pressure, like a balloon. Why not try to pop it?
One pathway was to take advantage of unstable proteins on the surface of the virus. Normally, protein spikes attract the healthy cell under attack and the two fuse together, opening the virus to transfer its genetic material. This disrupts the cell’s immune function and leads to AIDS. Abrams suspects the spike is primed like a mousetrap with bait and, when prodded a certain way, undergoes a change in structure.
“So I had this idea,” he says. “Let’s design a new molecule that will stick to these surface proteins on the virus but in a very particular way so that it tweaks those proteins and springs the trap.” The result is the irreversible destruction of the virus before it ever reaches a healthy cell.
DAVEI is engineered to bind to the surface proteins of the virus, like Chaiken’s other compounds. When that happens, the virus appears to be fooled into thinking it has found its target. But DAVEI doesn’t stop there. It hijacks the virus’ machinery, setting in motion its infection process prematurely. Because the virus is not actually attached to a cell, it spews out its genetic payload harmlessly. Like a popped balloon, the virus essentially deflates, the researchers speculate.
James A. Hoxie, a professor of medicine at the University of Pennsylvania and director of the Penn Center for AIDS Research, calls it a very clever design: “Their approach of not only entering the site, but triggering the machinery so that it activates inappropriately … is rather novel.”
“They’re poised to contribute very substantially to the basic understanding of how the virus is wired and … that gives us more tools for how to disrupt that virus,” Hoxie says of the researchers.
DAVEI has two main parts. The platform is the protein cyanovirin-N, which binds strongly to the virus. Added atop is the membrane-proximal external region (MPER), a small piece of viral protein itself that leads to breakup of the virus. The research was published last year in Antimicrobial Agents and Chemotherapy and in Retrovirology.
According to Abrams, “hunter/killer molecules” like DAVEI, which only target the virus and not healthy cells, could be used in topical microbicides to prevent infection.
While talk of new drugs is compelling, both Chaiken and Abrams say their primary focus is to better understand the inner workings of the notoriously tricky virus.
“There is an enormous need out there for new strategies,” says Abrams, whose work with Chaiken was funded with a $1.1 million National Institutes of Health grant awarded in 2009. “The more I learned about HIV, the more diabolical it seemed. It’s a fascinating machine.”
Adds Chaiken, “We must understand the inactivation mechanisms in order to guide better molecular designs.”
Going forward, the researchers are looking for new, im- proved platforms on which to build their HIV-busters. “In our group,” Chaiken says, “we’re trying to engineer the sons and daughters of DAVEI.”
See a video of how the DAVEI molecule “pops” HIV.