Newsday - May 8, 1992
Laurie Garrett
An international team has figured out what a key component of the AIDS virus looks like, paving the way for scientists to develop a new generation of drugs to fight AIDS.
Having deciphered the three-dimensional structure of the virus' key enzyme - called reverse transcriptase - the scientists hope the information will make it possible to tailor drugs to block the chemical. Such drugs would represent a vast improvement over current treatments.
"Knowing the structure of how a drug binds [to reverse transcriptase] is really an important tool in designing drugs. It makes our work more rational and, hopefully, more successful," said Dr. Margaret Johnston, head of AIDS drug development at the National Institute of Allergy and Infectious Diseases in Bethesda, Md.
Reverse transcriptase is crucial to the human immunodeficiency virus, which causes AIDS. Without it, the virus cannot hide inside the genetic material of cells that it infects, nor can it reproduce.
The three drugs legally available to treat HIV - AZT, ddI and ddC - all target reverse transcriptase. But their action against the vital enzyme is weak, and the HIV virus eventually mutates to create reverse transcriptase molecules that can get around the drugs.
"Certainly, drug companies really want to know the structure of reverse transcriptase to improve the drugs we have," said Dr. Stephen Hughes of the National Cancer Institute.
Hughes was part of the team that deciphered reverse transcriptase and published its structure in this week's issue of the British science journal Nature. He worked with colleagues from Tel Aviv University in Israel and the Center for Advanced Biotechnology and Medicine (CABM) in Piscataway, N. J.
The reverse transcriptase molecule is so small that seeing what it looks like - determining its structure - required a nuclear device called a synchrotron that shoots atomic subparticles at crystallized versions of the molecule and analyzes the diffraction patterns of those nuclear particles as they bounced off the crystal.
It has taken four years of crystallography in laboratories in New Jersey, Maryland and Israel; nuclear analysis at the Cornell High Energy Synchrotron Source; and mathematics calculations to pin it down, but the scientists now have a "picture" - computer-generated - of the enzyme. And they know where the active sites of the enzyme are located that are vital to its ability to reproduce the AIDS virus, Hughes said.
"It's really a very special time for us. We've been working on this thing for four years now - and we spent three of those years getting nothing," Dr. Alfredo Jacobo-Molina of CABM said. "And I was risking my career on this. People told me I was crazy . . . we'd never be able to do it. But it was really too important to let it go."
Hughes' lab is studying hundreds of HIV mutants to figure out what pieces of reverse transcriptase are so vital to the virus that it cannot survive if they are altered. This is crucial, Hughes said, because HIV has successfully mutated to resist all the drugs that have been tried so far.
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