La Jolla researchers' aborted efforts to cure the common cold may yield a SARS vaccine
By Penni Crabtree
UNION-TRIBUNE STAFF WRITER
August 10, 2003
PEGGY PEATTIE / Union-Tribune
Dave Matthews and Amy Patrick of Pfizer are part of a team that is using old research on the common cold to seek a treatment for SARS. The researchers hope to find a drug candidate before another outbreak occurs.
For more than a hair-tugging decade, at the cost of millions of dollars, a group of La Jolla researchers tried and failed to produce a cure for the common cold.
Now that scientific flop has turned into one of the more promising leads in the search for a treatment of SARS, the deadly virus that created a global panic earlier this year, claiming more than 800 lives and placing entire countries in virtual quarantine.
Some scientists are looking hard at a cache of experimental drug compounds first developed by La Jolla's former Agouron Pharmaceuticals as part of a failed cold virus research program. The biotechnology company, sold in 1999, now forms the nucleus of pharmaceutical giant Pfizer's local research campus.
"With the appropriate caveats, I think there are real possibilities here," said Cathy Laughlin, one of a team of researchers at the National Institute of Allergy and Infectious Diseases that is working to find a treatment for SARS, or Severe Acute Respiratory Syndrome. "The Pfizer compounds show a significant amount of activity, and I'd say they are a little bit ahead of everyone else on this."
Experts caution that Pfizer's compounds could take years to develop and may never pan out, but the need to find a treatment hasn't lost its urgency. Though the World Health Organization declared in June that SARS had been contained, experts warn that the virus could re-emerge later this year with the return of cool weather and the traditional flu season.
There are still no effective vaccines or treatments for the virus, which kills about 10 percent of those infected.
Pfizer's La Jolla campus houses a research team examining one or two of its most promising SARS drug compounds, as well as looking for ways to improve the best molecules or create new ones.
The researchers hope to find a drug candidate ready for advanced testing in humans if another SARS outbreak occurs.
"It's unheard of, the speed we are going at and the timelines we are trying to abide by," said Amy Patick,head of virology at Pfizer's La Jolla campus. "It's crazy, but we are doing it, because it could again become a life-and-death situation."
Although Pfizer is unlikely to profit from its research, the company's commitment to the project comes as the pharmaceutical industry faces increasing criticism about its efforts to fend off government price controls on high-priced medicines.
That Pfizer is a front-runner in the quest for a SARS treatment is also a testament to the serendipitous vagaries of drug research, where dead-end failures can resurrect into successes, and scientists never know where their research projects will lead.
For the past decade, well before its acquisition by Warner-Lambert and the subsequent merger that made it a subsidiary of Pfizer, Agouron had a drug discovery program targeting the human rhinovirus, a chief cause of the common cold.
Using a technique known as X-ray crystallography, Agouron explored a key protease – a type of enzyme – required for the replication of the rhinovirus, eventually mapping and publishing its structure in 1994. The company also developed several drug compounds to block it, one of which made it into midstage clinical studies in humans.
But the common cold proved to be a tough problem to solve, and the research effort was eventually shelved. All the research funding, and the scientific energy, appeared to have been wasted.
Then, last December, Dave Matthews, a scientific founder of Agouron and a distinguished research fellow at Pfizer, read a paper published by German researchers on the structure of a key protease from a pig coronavirus.
Matthews said the article caught his eye because the pig coronavirus protease appeared to share a similar structure and function to the human rhinovirus protease.
The Pfizer scientist found the similarities interesting, but at the time no connection had been made between the coronavirus and SARS, the unknown respiratory disease that was beginning to capture the interest of the scientific community and, ultimately, the world.
The first cases of SARS emerged in southern China in late November. In late February, a doctor spent one night in a Hong Kong hotel and contracted the disease.
He infected at least 16 people, who went on to spread the disease internationally. On March 12, the World Health Organization sent its first alert, reporting that 55 cases had been confirmed in one day.
On March 24, officials with the Centers for Disease Control and Prevention announced that tests indicated that the agent behind SARS was an unknown coronavirus.
"I remember coming in on Monday morning when the announcement was made over the radio that SARS was caused by a new coronavirus," Matthews said. "Obviously, I had this information from a few months earlier about the structure of the pig coronavirus protease, and putting two and two together "
Matthews speculated that the SARS virus protease needed for reproduction might have a similar structure to Pfizer's rhinovirus protease – and compounds developed to block the rhinovirus protease might work against SARS.
The German researcher had deposited the structure of the pig coronavirus protease in a public database, and Matthews retrieved the data and overlayed it with the coordinates for the rhinovirus protease, revealing telling similarities.
Pfizer researchers began exploring their extensive library of antiviral compounds to find a fit for the coronavirus protease. Meanwhile, a CDC consultant familiar with Pfizer's cold-virus work contacted the La Jolla researchers.
He told the Pfizer scientists that the CDC, along with NIAID and the U.S. Army Medical Research Institute of Infectious Diseases, had developed a test to screen for drug compounds that might be active against the virus. Thousands of experimental compounds, as well as already approved drugs, were being tested in hopes that something promising would emerge.
Did Pfizer have some compounds it could offer for screening, he asked.
Did it ever. By late March, the local Pfizer campus began providing to government researchers some 350 antiviral drug compounds for testing against SARS. Within two weeks, Pfizer had early results – some of the compounds had shown moderate activity against the virus.
Pfizer sent more potential compounds. By June, with the SARS epidemic on the wane, the company learned that about 10 of the potential drugs screened showed activity against the virus – in some cases "significant" activity – when tested in laboratory cell cultures.
Now Pfizer hopes that at least one of the compounds will succeed with SARS where they failed against the common cold. One crucial reason: the cold virus replicates swiftly, with symptoms that appear within 24 hours of infection, making it difficult to arrest virus reproduction early.
In contrast, the SARS virus has a much longer incubation period, taking up to several weeks to develop a full-blown infection, which provides a bigger window of opportunity to intervene.
Though government researchers acknowledge that Pfizer's compounds are promising, other researchers and companies also are pursuing treatments for SARS. Last month, German researchers announced that a drug used to treat multiple sclerosis may prove effective against SARS. And NIAID is working with Maryland-based GenVec on a vaccine to prevent SARS.
In recent days, San Diego's Structural GenomiX, a company that specializes in X-ray crystallography, mapped the main SARS virus protease and deposited it in a public database, making it easier for other drug companies to design drugs to fight SARS.
Whether Pfizer's SARS research effort ultimately yields a treatment, Matthews figures the company is ahead of the game.
"If you extrapolate and started from scratch like we did with the rhinovirus protease 10 years ago, you might argue that it would take you 10 years to get to this point with SARS," Matthews said. |
