S.D. Discovery Opens New Door to AIDS Drugs : Biotechnology: Researchers at La Jolla firm unlock structure of key element of AIDS virus. Patents filed on chemicals that may block HIV replication.
Researchers for a San Diego biotechnological company have discovered the structure of a key protein in the proliferation of the AIDS virus and have filed patents on more than 50 chemicals that may be able to block the enzyme’s action.
Although it could take years for the best of these to be tested in humans, the findings open the door to the computer-aided design of a whole new class of anti-AIDS drugs.
“I’m excited about this because this particular enzyme is one that’s been under-exploited, in terms of drug discovery and development,” said Margaret Johnston, chief of the AIDS developmental therapeutics branch at the National Institutes of Health.
“So I’m hoping that this will stimulate some new approaches to try to find potential drugs that block HIV replication,” Johnston said. (AIDS is caused by HIV, or human immunodeficiency virus.)
Researchers from Agouron Pharmaceuticals, in La Jolla on the Torrey Pines Mesa, published their findings in today’s edition of Science magazine.
Using X-rays and a mini-supercomputer, they found the three-dimensional structure of a tangled, 1,000-atom protein called RNase H. Their computer picture of the molecule showed a long, deep groove, the “receptor” site through which the enzyme locks onto its target to function.
RNase H is responsible for destroying the AIDS virus’s genetic material, RNA, after it is no longer needed inside the infected cell. This is a key step to the virus commandeering the cell’s own genetic code, to order it to produce more virus.
Without the RNase H activity, HIV would be unable to reproduce at all, stopping the progression toward AIDS and death.
Indeed, blocking an enzyme is how the existing anti-AIDS drug AZT functions, by interfering with another part of this viral replication process.
Scientists at Agouron are especially excited about having already identified a whole class of metal-containing chemicals that can block RNase H’s receptor site, said Peter Johnson, company president.
On Wednesday, the company filed for patents on more than 50 specific possibilities, as well as on any other molecules with similar chemical properties, Johnson said.
It was the structural breakthrough with the enzyme that made this proprietary discovery possible, he added.
“When you look back from the standpoint of seeing a new generation of anti-HIV drugs in the clinic, and ask what were the really seminal events that pointed in the direction of these, the report of this structure will in fact be one of those events,” Johnson predicted.
The hope is that one of the dozens of chemicals Agouron is testing will lock very specifically onto RNase H’s active site. The fit needs to be as close to perfect as possible, to minimize the chance of side effects from an anti-RNase H drug.
With AZT, the viral replication process is stopped but so is replication of human genetic material, DNA, noted Didier Trono, an AIDS researcher at the Salk Institute.
“AZT doesn’t block (the enzyme) specifically enough, and that’s why patients have side effects like bone marrow suppression,” Trono said. “Because production of DNA somehow is also blocked by AZT.”
Trono agreed with NIH’s Johnston that Agouron’s structural work could lead to a whole new class of anti-AIDS drugs. But the work will not come overnight, he cautioned.
“Designing a compound that can block a reaction in a tube is one thing. From that stage to bringing this compound into patients is quite another thing,” Trono said. “So I think it’s an important piece of work, but people need to be conscious of everything that’s left to be done before this work can result in drugs that can be applied to humans.”
Agouron has done similar work at finding the structure of a protein that is key to reproduction of cells in proliferative diseases such as cancer and psoriasis.
In that research, it has taken about three years to get from the structural phase to the earliest clinical trials of a drug designed at the company, Johnson said. He wouldn’t predict if an anti-RNase H drug would take that long, but he noted that the work so far has moved much more quickly than anyone would have predicted.
From the first crystallization of RNase H in October to having final map of the structure took less than 100 days, he said.
It took more than a year for previous proteins to be mapped out with the technique, called X-ray crystallography.
This time, luck played a big part. Notably, a uranium-containing compound that the researchers had to use to complete the X-ray work turned out to lock onto RNase H very effectively.
This pointed to the entire class of compounds that will be tested as potential drugs to inhibit the enzyme, said David A. Matthews, the senior author on the report in Science.
Producing the paper with Matthews were Jay F. Davies II, Zuzana Hostomska, Zdenek Hostomsky and Steven R. Jordan.
RNase H is only the second HIV enzyme to be structurally characterized, and is one of only four known to be essential to replication.
The first 3-D map of an HIV enzyme, protease, was completed about a year ago. This already has resulted in the design, one atom at a time, of several potential drugs to block protease’s role in viral replication, Johnston said.
The AIDS virus destroys the body’s immune system, making victims susceptible to death from infection. About 168,000 Americans have been diagnosed with AIDS since 1982, more than 31,500 of them in California. Most have already died.
Matthews said being able to do research that might help many people is gratifying. But, for an X-ray crystallographer, so is deciphering the structure of a protein, he said.
“Whenever you see a new protein that nobody’s ever seen before, it’s always a little bit exciting,” Matthews said. “I guess it’s the 20th-Century analog of the pioneer who crosses the mountain and sees what’s on the other side for the first time. You’re really seeing something that nobody’s ever seen before.”
Agouron was founded in 1984 specifically to explore the emerging field of rational drug design. Its founders include biologists John Abelson and Melvin Simon at the California Institute of Technology, and chemist Joseph Kraut of UC San Diego.
It has drug research and development agreements with drug firm Eli Lilly, which owns 7% of the firm’s stock. Agouron has lost about $15 million over the last three fiscal years, with a high of $6.2 million in 1990. The company expects those losses to continue for several years, until its drugs are on the market.
How RNase H Works
Once the AIDS virus is inside a cell, it can reproduce only by using the cell’s own genetic machinery. RNase H is the smaller part of a two-ended molecule that converts the virus’ RNA genetic code into a double-stranded DNA fragment, usable by the cell.
A. The molecule’s large end, reverse transcriptase, converts the viral RNA code into a strand of DNA. But the RNA and DNA strands are linked.
B. The small end, the RNase H, decomposes the RNA strand.
C. The large end makes another DNA strand, joined to the first. Later, two other enzymes put the fragment into the cell’s DNA; the cell then builds new viruses.
