San Francisco Chronicle - The Voice of the West, 901 Mission Street, San Francisco, CA 94119 - Friday, April 18, 1997 - Page A4
David Perlman, Chronicle Science Editor

For the first time, the scientists said, they have managed to take apart a complex protein on the "envelope" that coats the virus and have determined its structure in unprecedented detail.

The region of the molecule the scientists studied is called a fusion protein because it governs the ability of HIV, the virus that causes AIDS, to fuse with the protective membrane of an immune system cell and infect it.

And because that protein region apparently does not undergo the constant changes that are typical of other regions on the viral envelope, its stability should help drug designers overcome the frustrating problem of resistance that has rendered many AIDS drugs useless.

"Without a doubt, this represents an important development in the recent explosion of new information about the structure of HIV," said Dr. Mark Goldsmith, a physician and AIDS researcher at the University of California's Gladstone Institute of Virology and Immunology in San Francisco.

"It offers a powerful and compelling target for rational drug design," he said.

The structural biologists who discovered the crucial region of the fusion protein are publishing their report in the journal Cell today. They include Dr. David Chan and Dr. Peter S. Kim of the Whitehead Institute for Biomedical Research and the Howard Hughes Medical Institute in Cambridge, Mass.

HIV is actually little more than a package of genetic material contained in an envelope made up of various proteins whose molecular structures rapidly undergo mutation.

As a result, all the successful virus- fighting drugs developed so far have attacked the genetic machinery inside the virus rather than its outer coat, and researchers have failed to find any drug that can successfully disarm the viral envelope.

One part of the envelope protein, known as gp120, allows the virus to bind to human cells of the immune system, while another part, called gp41, enables the virus to fuse with the cells it attacks and to penetrate their protective membranes.

The Whitehead researchers first crystallized the gp41 portion of the complex protein, and with the techniques of X-ray crystallography, they created images of the protein's structure that showed precise details of unexpected cavities inside.

"Until we saw the images, we didn't know that those cavities existed," Kim said. "They could be key targets for the development of new antiviral drugs."

Drug designers, using the information on the detailed structure of the cavities together with powerful computer programs, should be able to develop drugs that fit the cavities and thereby thwart the virus attack, the Whitehead researchers said.

To speed the drug discovery process, Kim and Chan said, they are making precise three-dimensional information about the fusion protein widely available to other scientists through the Protein Data Bank maintained at the Brookhaven National Laboratory in New York.

In a discussion of the Whitehead group's discovery yesterday, Goldsmith at the Gladstone Institute noted that the new drugs it may make possible would be still another weapon in the arsenal of drugs that are now keeping AIDS patients alive and healthier than ever.

All the other anti-viral drugs -- including the new protease inhibitors -- are designed to disable the genetic machinery inside HIV, and thus prevent the virus from reproducing, Goldsmith noted. New drugs designed to strike at the outer coat of the virus and thereby disable its ability to invade the immune system would give patients a valuable new addition to the combination therapies that have recently become available.
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