Draga
12-19-04, 01:49 AM
They may prevent virus from copying
PISCATAWAY, N.J. -- To change the world, Eddy Arnold has always tried to think small.
For nearly 20 years, the Rutgers University chemist has obsessively dismantled the AIDS virus to untangle its deadly submicroscopic machinery.
It is there, in the complex world of the minuscule, that he believes he finally has found a magic bullet that stops AIDS in its tracks.
Arnold and his coterie of researchers have developed what they regard as three revolutionary AIDS drugs, each part of a family they call DAPY, which rhymes with happy.
The drugs, they believe, can destroy HIV, the deadly virus that causes AIDS.
The drugs do as HIV does when it devours immune systems: They change shape. Put another way, DAPYs are a master key that can fit any strand of the virus, regardless of how it tries to disguise itself.
"We're onto something very, very special," Arnold said.
Understanding and controlling the flexibility in a treatment is crucial because HIV's biggest challenge to science and medicine has been its ability to consistently mutate, outrunning any drug or vaccine designed to quash it. Unlike other treatments that focus on blocking HIV from entering healthy cells or on containing contaminated ones, DAPYs douse a lighted firecracker by interfering with any of the 20,000 steps HIV takes to copy itself at warp speed.
At the core of this discovery is reverse transcriptase -- the villain in this story and a submicroscopic protein not normally found in healthy human cells. The team believes it is the ideal protein to disable because it offers so many opportunities to be blocked.
The most promising of the three DAPY drugs in the family is a new supercompound known as R278474.
Because DAPYs can be delivered in just one pill instead of the present drug cocktail taken by millions of AIDS patients, Arnold and others say they think they are a step closer to the goal of creating a cheaper, more effective way to stay ahead of the epidemic.
Tests conducted internally at Johnson & Johnson indicate the drug is a snap to synthesize, is easily absorbed with minimal side effects and shows promise as a once-daily, low-dose oral treatment.
For researchers on the front line, R278474 and its cousins may be that magic bullet.
"This could be it," said Stephen Smith, a doctor and scientist who directs the department of infectious disease at Saint Michael's Medical Center in Newark, N.J. "We're all looking for the next class of drugs."
Smith manages dozens of clinical trials testing AIDS treatments and said the idea underlying the new reverse transcriptase inhibitors makes sense.
"Reverse transcriptase is very important in the biology of AIDS," Smith said. "If you can really inhibit reverse transcriptase, you can stop AIDS."
Disease harder to fight
It will take an extraordinary remedy to beat AIDS for good. After being held in check for 17 years -- first by workhorse medications such as AZT, introduced in 1987, and then by drug cocktails, available since 1996 -- the disease is becoming resistant to such treatments.
Worldwide, acquired immune deficiency syndrome has killed 20 million people since appearing in the United States in 1981. Forty million live with the disease, according to U.N. statistics.
In the developing world, where many patients cannot afford even generic versions of AIDS medications, the virus kills people during their most productive years and decimates whole regions.
Arnold, 47, thinks he can solve some of these problems.
Team of researchers
Arnold studies the structure of biological molecules -- the proteins that are the beating heart of the human immunodeficiency virus -- at Rutgers University's Busch Campus in Piscataway.
He does this through X-ray crystallography, an increasingly popular technique used in chemistry and biology to determine the structure of molecules.
Reverse transcriptase is a highly complex machine compared with HIV's other proteins, protease and integrase. Composed of chains containing combinations of 20 amino acids, it is folded in unpredictable ways. Scientists think there are patterns in these ribbons, but no one has deciphered them.
Reverse transcriptase inhibitors interfere with an enzyme that HIV needs to copy itself. If the enzyme fails to function, HIV cannot insert itself into a human host cell and will die.
Arnold established his laboratory at Rutgers in 1987 with his biologist wife, Gail Ferstandig, and set off building what is now a 30-member research team that partners with Janssen Pharmaceutica and Tibotec-Virco NV, both subsidiaries of Johnson & Johnson.
Arnold's first big move was forming a partnership, also in 1987, with Stephen Hughes, a leading virologist and AIDS researcher at the National Cancer Institute in Frederick, Md.
In 1990, the collaboration added Paul Janssen, a legendary drug pioneer whose dream, according to Arnold, was to devise a drug that could be distributed cheaply in the developing world.
That dream and Arnold's team ultimately produced R278474, or ripilvirine, Janssen's favorite anti-AIDS compound and the newest DAPY. The compounds are so named because they have diarylpyrimidine at their core. The other two compounds -- dapivirine or TMC-120, and etravirine or TMC-125 -- have gone through early phases of clinical trials. Making it through those experiments, something most drugs don't accomplish, shows the compounds hold great promise to win federal approval.
Details of R278474 will be published early next year in the Journal of Medicinal Chemistry to be dedicated to "Dr. Paul," as the Belgian doctor-scientist, who died in 2003, was known to colleagues. On Nov. 11, Arnold's team prepublished details in the electronic edition of the journal. The article represents the pinnacle of their work.
A key contributor
R278474 never would have existed without Janssen's work 14 years earlier.
In 1990, he published a paper in the science journal Nature describing a new drug that blocked HIV's key protein, reverse transcriptase. Problem was, the compounds caused mutations to occur. The drugs failed to recognize and treat the mutant strains.
Unable to see this relationship between the drug and the killer virus under a microscope, Janssen needed a scientist to make a crystal that would combine reverse transcriptase with his experimental compound. He was told there were only three people who could do it.
Arnold was one of them.
Crystallography, which involves rendering materials into well-ordered crystals and then fathoming their atomic structures, may be as much art as science.
The Picasso that Arnold's lab was chasing was the crystal structure of reverse transcriptase.
"It took us from 1987 until mid-1991 to get RT crystals that were useful for getting a detailed structure," Arnold said. "But it took until mid- to late 1992 to solve the detailed structure from these crystals. It was very technically challenging."
Competition emerges
Compounding the tension was a team of researchers at the lab of eminent scientist Thomas Steitz at Yale University who also were on the case.
In May 1992, Arnold and his team published a paper showing what amounted to a rough map of the reverse transcriptase molecule.
The following month, the Steitz team published a paper with greater details, revealing the overall structure of the molecule. The scientific community hailed the paper as a breakthrough.
Undeterred, Arnold's lab came back in June 1993 with a tour de force. The paper showed not just reverse transcriptase, but the molecule bound with double-stranded DNA -- in essence, a snapshot of the protein in action as it co-opts a healthy cell.
"At the time, it filled in a lot of gaps in terms of details of what is where in RT -- where drug-resistant mutations are located," Arnold said.
The paper made Arnold a star and earned him permanent tenure at Rutgers. It also helped him win financing from the National Institutes of Health and pharmaceutical companies. More money meant more staff. He also was given more space in his building.
It didn't make him rich, though, and he will not receive royalties or any other fees if the DAPYs are commercially successful.
He doesn't like to discuss specifics, but his salary is consistent with that of other top professors at Rutgers -- meaning he earns well into the six figures, but far less than the university's football and basketball coaches.
After the 1993 paper, the Arnold team produced many variant structures of the reverse transcriptase molecule, or new looks at the virus's mutating dances. It was work that led to the reverse transcriptase inhibitors.
But Arnold's team didn't know that at the time.
Clinging to the concept
In 1996, Arnold suddenly found his research out of step.
The introduction of protease inhibitors lowered the profile of the reverse transcriptase research.
When combined with other drugs in the so-called AIDS cocktails, protease inhibitors are highly effective in extending lives. Their efficacy produced the flawed perception that the disease finally had been beaten. It also nearly killed financing for research on new versions of older drugs.
After protease inhibitors were featured at an international AIDS meeting in July 1996 in Vancouver, British Columbia, Wall Street's enthusiasm for other research flagged.
But science had tamed the tiger only in places where patients could afford medications.
Arnold's team hung on.
They knew what they had to do: thwart reverse transcriptase. And they knew they needed a magical crystal, of sorts, to light their way.
A crystallographer, with just the right mix of chutzpah, luck and intelligence, can believe he has a shot at understanding any living thing.
Even if a molecule is too tiny to see with a microscope, a crystallographer can figure out its shape and composition. Now it would be the team's job to use crystallography to figure out exactly how the DAPYs worked.
State-of-the-art facility
The battleground would be a tiny room at the Cornell High Energy Synchrotron Source in Ithaca, N.Y., a favorite destination for Rutgers crystallographers for more than a decade.
CHESS is one of the world's leading centers for X-ray research in biology and materials science, a 23-year-old facility in Wilson Laboratory under a football field on the vast campus.
The facility's workhorse is the synchrotron, a massive, ring-shaped machine that actually is the size of the field under which it sits. It accelerates subatomic particles almost to the speed of light, producing synchrotron radiation -- a form of light researchers shine on molecules, atoms, crystals and other forms of new materials to understand their structure and behavior.
The radiation gives researchers unparalleled power and precision to probe the fundamentals of matter. The light is a million times brighter than sunlight and a billion times greater than the radiation from a typical lab X-ray. The emerging beams are just a few thousandths of a millimeter across and are emitted in extremely short pulses, typically 10 to 100 picoseconds (trillionths of a second) in length.
The team's work on the "Super DAPY" crystal R278474 was published in May 2004 in the Journal of Medicinal Chemistry. By summer, molecular flexibility was the talk of a meeting at the National Institutes of Health. It remains a popular theme among researchers.
Meanwhile, TMC-120 and TMC-125 -- the older cousins to the Super DAPY -- have shown great promise in Phase I and Phase II trials in the past two years.
Smith, the AIDS expert in Newark, said clinical trials testing safety and effectiveness of TMC-125 are moving apace. He already is enrolling patients for Phase III, the all-important stage in which the federal government assesses patients before approving or rejecting a drug.
Any company embarking on such a multimillion-dollar endeavor is committed to bringing the drug to market, Smith said. Johnson & Johnson officials confirm TMC-120 and TMC-125 are of major interest to them. But they won't discuss R278474.
In the end, one or more of the DAPY compounds could represent Johnson & Johnson's first foray into the multibillion-dollar market for AIDS drugs. If TMC-125 moves successfully through its third phase, which would take about two years, it could be approved by the Food and Drug Administration in 2007.
. . . . . . .
Kitta MacPherson writes about science for The Star-Ledger of Newark, N.J. She can be reached at kmacpherson@starledger.com.
PISCATAWAY, N.J. -- To change the world, Eddy Arnold has always tried to think small.
For nearly 20 years, the Rutgers University chemist has obsessively dismantled the AIDS virus to untangle its deadly submicroscopic machinery.
It is there, in the complex world of the minuscule, that he believes he finally has found a magic bullet that stops AIDS in its tracks.
Arnold and his coterie of researchers have developed what they regard as three revolutionary AIDS drugs, each part of a family they call DAPY, which rhymes with happy.
The drugs, they believe, can destroy HIV, the deadly virus that causes AIDS.
The drugs do as HIV does when it devours immune systems: They change shape. Put another way, DAPYs are a master key that can fit any strand of the virus, regardless of how it tries to disguise itself.
"We're onto something very, very special," Arnold said.
Understanding and controlling the flexibility in a treatment is crucial because HIV's biggest challenge to science and medicine has been its ability to consistently mutate, outrunning any drug or vaccine designed to quash it. Unlike other treatments that focus on blocking HIV from entering healthy cells or on containing contaminated ones, DAPYs douse a lighted firecracker by interfering with any of the 20,000 steps HIV takes to copy itself at warp speed.
At the core of this discovery is reverse transcriptase -- the villain in this story and a submicroscopic protein not normally found in healthy human cells. The team believes it is the ideal protein to disable because it offers so many opportunities to be blocked.
The most promising of the three DAPY drugs in the family is a new supercompound known as R278474.
Because DAPYs can be delivered in just one pill instead of the present drug cocktail taken by millions of AIDS patients, Arnold and others say they think they are a step closer to the goal of creating a cheaper, more effective way to stay ahead of the epidemic.
Tests conducted internally at Johnson & Johnson indicate the drug is a snap to synthesize, is easily absorbed with minimal side effects and shows promise as a once-daily, low-dose oral treatment.
For researchers on the front line, R278474 and its cousins may be that magic bullet.
"This could be it," said Stephen Smith, a doctor and scientist who directs the department of infectious disease at Saint Michael's Medical Center in Newark, N.J. "We're all looking for the next class of drugs."
Smith manages dozens of clinical trials testing AIDS treatments and said the idea underlying the new reverse transcriptase inhibitors makes sense.
"Reverse transcriptase is very important in the biology of AIDS," Smith said. "If you can really inhibit reverse transcriptase, you can stop AIDS."
Disease harder to fight
It will take an extraordinary remedy to beat AIDS for good. After being held in check for 17 years -- first by workhorse medications such as AZT, introduced in 1987, and then by drug cocktails, available since 1996 -- the disease is becoming resistant to such treatments.
Worldwide, acquired immune deficiency syndrome has killed 20 million people since appearing in the United States in 1981. Forty million live with the disease, according to U.N. statistics.
In the developing world, where many patients cannot afford even generic versions of AIDS medications, the virus kills people during their most productive years and decimates whole regions.
Arnold, 47, thinks he can solve some of these problems.
Team of researchers
Arnold studies the structure of biological molecules -- the proteins that are the beating heart of the human immunodeficiency virus -- at Rutgers University's Busch Campus in Piscataway.
He does this through X-ray crystallography, an increasingly popular technique used in chemistry and biology to determine the structure of molecules.
Reverse transcriptase is a highly complex machine compared with HIV's other proteins, protease and integrase. Composed of chains containing combinations of 20 amino acids, it is folded in unpredictable ways. Scientists think there are patterns in these ribbons, but no one has deciphered them.
Reverse transcriptase inhibitors interfere with an enzyme that HIV needs to copy itself. If the enzyme fails to function, HIV cannot insert itself into a human host cell and will die.
Arnold established his laboratory at Rutgers in 1987 with his biologist wife, Gail Ferstandig, and set off building what is now a 30-member research team that partners with Janssen Pharmaceutica and Tibotec-Virco NV, both subsidiaries of Johnson & Johnson.
Arnold's first big move was forming a partnership, also in 1987, with Stephen Hughes, a leading virologist and AIDS researcher at the National Cancer Institute in Frederick, Md.
In 1990, the collaboration added Paul Janssen, a legendary drug pioneer whose dream, according to Arnold, was to devise a drug that could be distributed cheaply in the developing world.
That dream and Arnold's team ultimately produced R278474, or ripilvirine, Janssen's favorite anti-AIDS compound and the newest DAPY. The compounds are so named because they have diarylpyrimidine at their core. The other two compounds -- dapivirine or TMC-120, and etravirine or TMC-125 -- have gone through early phases of clinical trials. Making it through those experiments, something most drugs don't accomplish, shows the compounds hold great promise to win federal approval.
Details of R278474 will be published early next year in the Journal of Medicinal Chemistry to be dedicated to "Dr. Paul," as the Belgian doctor-scientist, who died in 2003, was known to colleagues. On Nov. 11, Arnold's team prepublished details in the electronic edition of the journal. The article represents the pinnacle of their work.
A key contributor
R278474 never would have existed without Janssen's work 14 years earlier.
In 1990, he published a paper in the science journal Nature describing a new drug that blocked HIV's key protein, reverse transcriptase. Problem was, the compounds caused mutations to occur. The drugs failed to recognize and treat the mutant strains.
Unable to see this relationship between the drug and the killer virus under a microscope, Janssen needed a scientist to make a crystal that would combine reverse transcriptase with his experimental compound. He was told there were only three people who could do it.
Arnold was one of them.
Crystallography, which involves rendering materials into well-ordered crystals and then fathoming their atomic structures, may be as much art as science.
The Picasso that Arnold's lab was chasing was the crystal structure of reverse transcriptase.
"It took us from 1987 until mid-1991 to get RT crystals that were useful for getting a detailed structure," Arnold said. "But it took until mid- to late 1992 to solve the detailed structure from these crystals. It was very technically challenging."
Competition emerges
Compounding the tension was a team of researchers at the lab of eminent scientist Thomas Steitz at Yale University who also were on the case.
In May 1992, Arnold and his team published a paper showing what amounted to a rough map of the reverse transcriptase molecule.
The following month, the Steitz team published a paper with greater details, revealing the overall structure of the molecule. The scientific community hailed the paper as a breakthrough.
Undeterred, Arnold's lab came back in June 1993 with a tour de force. The paper showed not just reverse transcriptase, but the molecule bound with double-stranded DNA -- in essence, a snapshot of the protein in action as it co-opts a healthy cell.
"At the time, it filled in a lot of gaps in terms of details of what is where in RT -- where drug-resistant mutations are located," Arnold said.
The paper made Arnold a star and earned him permanent tenure at Rutgers. It also helped him win financing from the National Institutes of Health and pharmaceutical companies. More money meant more staff. He also was given more space in his building.
It didn't make him rich, though, and he will not receive royalties or any other fees if the DAPYs are commercially successful.
He doesn't like to discuss specifics, but his salary is consistent with that of other top professors at Rutgers -- meaning he earns well into the six figures, but far less than the university's football and basketball coaches.
After the 1993 paper, the Arnold team produced many variant structures of the reverse transcriptase molecule, or new looks at the virus's mutating dances. It was work that led to the reverse transcriptase inhibitors.
But Arnold's team didn't know that at the time.
Clinging to the concept
In 1996, Arnold suddenly found his research out of step.
The introduction of protease inhibitors lowered the profile of the reverse transcriptase research.
When combined with other drugs in the so-called AIDS cocktails, protease inhibitors are highly effective in extending lives. Their efficacy produced the flawed perception that the disease finally had been beaten. It also nearly killed financing for research on new versions of older drugs.
After protease inhibitors were featured at an international AIDS meeting in July 1996 in Vancouver, British Columbia, Wall Street's enthusiasm for other research flagged.
But science had tamed the tiger only in places where patients could afford medications.
Arnold's team hung on.
They knew what they had to do: thwart reverse transcriptase. And they knew they needed a magical crystal, of sorts, to light their way.
A crystallographer, with just the right mix of chutzpah, luck and intelligence, can believe he has a shot at understanding any living thing.
Even if a molecule is too tiny to see with a microscope, a crystallographer can figure out its shape and composition. Now it would be the team's job to use crystallography to figure out exactly how the DAPYs worked.
State-of-the-art facility
The battleground would be a tiny room at the Cornell High Energy Synchrotron Source in Ithaca, N.Y., a favorite destination for Rutgers crystallographers for more than a decade.
CHESS is one of the world's leading centers for X-ray research in biology and materials science, a 23-year-old facility in Wilson Laboratory under a football field on the vast campus.
The facility's workhorse is the synchrotron, a massive, ring-shaped machine that actually is the size of the field under which it sits. It accelerates subatomic particles almost to the speed of light, producing synchrotron radiation -- a form of light researchers shine on molecules, atoms, crystals and other forms of new materials to understand their structure and behavior.
The radiation gives researchers unparalleled power and precision to probe the fundamentals of matter. The light is a million times brighter than sunlight and a billion times greater than the radiation from a typical lab X-ray. The emerging beams are just a few thousandths of a millimeter across and are emitted in extremely short pulses, typically 10 to 100 picoseconds (trillionths of a second) in length.
The team's work on the "Super DAPY" crystal R278474 was published in May 2004 in the Journal of Medicinal Chemistry. By summer, molecular flexibility was the talk of a meeting at the National Institutes of Health. It remains a popular theme among researchers.
Meanwhile, TMC-120 and TMC-125 -- the older cousins to the Super DAPY -- have shown great promise in Phase I and Phase II trials in the past two years.
Smith, the AIDS expert in Newark, said clinical trials testing safety and effectiveness of TMC-125 are moving apace. He already is enrolling patients for Phase III, the all-important stage in which the federal government assesses patients before approving or rejecting a drug.
Any company embarking on such a multimillion-dollar endeavor is committed to bringing the drug to market, Smith said. Johnson & Johnson officials confirm TMC-120 and TMC-125 are of major interest to them. But they won't discuss R278474.
In the end, one or more of the DAPY compounds could represent Johnson & Johnson's first foray into the multibillion-dollar market for AIDS drugs. If TMC-125 moves successfully through its third phase, which would take about two years, it could be approved by the Food and Drug Administration in 2007.
. . . . . . .
Kitta MacPherson writes about science for The Star-Ledger of Newark, N.J. She can be reached at kmacpherson@starledger.com.