Designer Drug Bites HIV Achilles' Heel

From the WebMD Archives

Jan. 11, 2001 -- A different way to attack the AIDS virus could be used to fight other viruses as well. The strategy may lead not only to new antiviral drugs, but also to vaccines against some of the world's worst diseases.

MIT Whitehead Institute researcher Peter S. Kim, PhD, and co-workers took advantage of earlier work showing that some viruses pierce human cells with a harpoon-like structure. This coiled structure -- which is shaped like three hairpins bundled together -- pops out of the virus just before spearing its target. Kim's team designed a molecule that sticks to part of the harpoon and prevents it from springing open into its hairpin form. HIV exposed to this molecule loses its ability to infect new cells.

"Now people will take this molecule and move it forward to do the things necessary to put it into animals for testing," Kim tells WebMD. "I certainly hope we have an impact on the HIV epidemic."

An experimental AIDS drug now in the final stages of human testing -- pentafuside or T-20 -- also attacks the coiled structure on HIV. But the new molecule developed by Kim's team -- dubbed 5-Helix -- attaches to a completely different part of the pre-hairpin structure. This is no small difference. HIV is infamous for its ability to outsmart even the most cleverly designed drugs, and new targets for attack are desperately needed by patients who are running out of lifesaving treatment options.

Eric Hunter, PhD, is director of the center for AIDS research at the University of Alabama at Birmingham. He also serves as a scientific adviser to T-20 manufacturer Trimeris Inc. "This really represents a whole new area for drug development against a number of viruses," Hunter tells WebMD. "The realization that this is a target is stimulating a lot of research activity in a lot of places. This is a very exciting time to be involved in this type of work."

Kim notes that the three-hairpin bundle is used by several other viruses that infect cells by fusing their outer surfaces to the outer membrane of human cells. "It's not found in hepatitis C virus, but it's found in Ebola virus," he says. "At the end of last year, we showed it was present in human respiratory syncytial virus, which is a major cause of infant mortality. And HIV is known to be very similar to influenza virus. So it is plausible that the 5-Helix strategy could be applied to a wide range of viruses."

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Kim also hopes that the 5-Helix strategy could be used to create an AIDS vaccine. This is because the molecule mimics the HIV Achilles' heel -- a crucial part of the virus normally hidden from the immune system. This crucial target becomes exposed just as the virus prepares to attack. Antibodies against 5-Helix also might attack this structure.

"The notion here is that antibodies against the HIV envelope have not proven very effective, because the virus can rapidly mutate and escape neutralization," Kim explains. "However, there are regions of the envelope that [the virus cannot afford to mutate], but those are normally buried deep inside. But during the [infection] process, these conserved regions become exposed.

"We and others have been interested for some time in coming up with [vaccines] that would elicit antibody responses against these highly conserved regions. 5-Helix might represent one way to do that," he says.

Kim and Hunter both note that 5-Helix is not yet ready for testing. "I personally look at this much more as proof of concept than as a lead molecule for drug discovery," Hunter says.

Kim soon may be in a position to change this. Beginning next month, he will move to a new job: head of worldwide research and development for pharmaceutical giant Merck.

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