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Possible New HIV Drug Stops Breaking And Entering
Maggie Fox, Health and Science Correspondent
January 11, 2001
WASHINGTON (Reuters) - A designer protein that stops the AIDS virus from breaking and entering might make it as a last-ditch weapon in the arsenal against HIV, researchers said on Thursday.

They said they had engineered a protein that prevents the virus from attaching itself to the cells it attacks. Their protein, if launched as a drug, would join a new category of HIV drugs known as entry inhibitors.

Tweaking the protein, called 5-Helix, might make it work against a range of viruses, including influenza, said the researchers at the Howard Hughes Medical and Whitehead Institutes at the Massachusetts Institute of Technology .

Dr. Peter Kim, who led the research, said the protein was a long way from being tested in people.

"What is needed now is for someone to take this and start to do the things that are required for animal testing," he said in a telephone interview.

So far the researchers are not working with any drug company, said Kim, who is leaving MIT to head worldwide research and development for Merck . He said 5-Helix is a protein, which is too large a molecule to be absorbed orally. It would have to be injected, like the only fusion inhibitor close to marketing approval, Trimeris Inc.'s T-20.

"It is less convenient than swallowing a pill," Kim said. "So it would probably be used as a salvage therapy, which is used when the existing armamentarium of drugs against HIV are no longer effective."

The researchers, who reported their findings in the journal Science, said it might also be used in a gene therapy approach to treating HIV. This would involve putting altered genes into the body.

Spring-Loaded Mechanisms

Like T-20, 5-Helix targets the gp41 protein, a key part of the spring-loaded mechanism that HIV uses to get into cells.

"In 1993 we showed that the flu virus uses a spring-loaded mechanism to infect cells," Kim said.

"The protein springs out and part of the protein inserts in the cell membrane and then the mechanism snaps back to form a hairpin-like mechanism. This brings together the viral and the cell membranes. Now the two membranes are next to each other and then they somehow fuse -- we don't quite understand how."

After that, the virus injects its genetic material into the victim cell and makes the cell crank out copy after copy of the virus.

"It turns out that HIV uses a very similar mechanism," Kim said. He said it was if someone pushed their hand forward through a ring and then pulled it back to the shoulder -- the arm would form a hairpin-like structure and clasp the ring.

T-20 and 5-Helix target two different points on this structure, Kim said. "They can get in the way and block hairpin formation," he said.

If the virus cannot fuse to a cell, it cannot inject its genes and infection stops.

Kim said 5-Helix seemed to work against a broad range of HIV variants. The virus has evolved into numerous forms and sometimes drugs work well only against certain of these.

The researchers deliberately designed 5-Helix, knowing what the gp41 protein looked like. They literally built the genetic sequence of a protein that would fit into gp41 and block it, then inserted this artificial DNA into bacteria and made them produce the synthetic protein.

"It's not that hard," Kim said.

He said he thought slight changes in the design might make 5-Helix work against flu and other viruses.



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