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Microbicide Protein Identified
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CWRU researchers to announce breakthrough in anti-HIV gel for women
Regina McEnery February 04, 2008 00:01AM
http://blog.cleveland.com
AIDS researchers solved a major stumbling block in the production of a vaginal gel, raising hopes that the compound can one day find its way to millions of poor women at risk for HIV.
At a major AIDS conference in Boston today, scientific players that include Case Western Reserve University will describe their dogged and ultimately successful attempt to reinvent an anti-HIV molecule known as PSC-Rantes that though potent, was also incredibly expensive to produce.
"We always felt we had something very promising here," said Dr. Michael Lederman, one of the key collaborators on the project and the director of the Case Center for AIDS Research based at University Hospitals.
"We have been effectively dealing with those challenges and resolving them. That is what it takes to develop a strategy. When we started this, no one thought this would make any sense."
The three cheaper versions were found using a relatively new technique that generates a vast pool of like-minded biological candidates bearing some resemblance to the Rantes molecule. Not only did these molecules appear to be just as good as the Rantes molecule in preventing viral entry into cells, but they also didn't come with the complicated assembling instructions of their Cadillac-style cousin.
Along with the Conference on Retroviruses and Opportunistic Infections that opened Sunday, the research is being presented at a microbicides conference in India later this month.
Microbicides are gels, creams and other compounds that women can apply before intercourse to prevent transmission of HIV. Governments and private foundations like the Bill and Melinda Gates Foundation have committed millions of dollars to finding products that will work, but like the struggling AIDS vaccine field, an effective microbicide has defied science.
Most of the first-generation antiviral drug attempts for women relied on a detergentlike substance to burst the protective covering surrounding HIV cells. They performed poorly in clinical trials and may have even put some women at greater risk for HIV.
The PSC-Rantes, a manufactured molecule modeled after a naturally occurring protein, works differently. Rather than killing the virus, it shutters the molecular receptors that HIV needs to get inside cells. Without a host, the virus can't replicate and dies.
Primate studies completed by Lederman's collaborator at Tulane University found that the PSC-Rantes prevented vaginal transmission of simian HIV, the strain of the killer virus that infects monkeys. Scientists coated the vaginal surfaces of monkeys with the drug 15 minutes before exposing them to the simian strain. The results were published in 2004.
But researchers working on the project saw little chance of the drug making it to clinical trials because of the heavy production costs.
This caveat threatened to shelve their years of hard work when Lederman's collaborator Oliver Hartley, a biochemist at the University of Geneva, Switzerland, stepped in and suggested they use a technique called phage display that would allow them to generate cheaply a whole family of molecules. For the better part of a year, Hartley's eight-person laboratory suspended all their other projects to identify naturally occurring molecules as powerful as PSC-Rantes.
They initially identified about 30, then narrowed their list to three. In addition to being potent antiviral agents, two of the molecules also don't appear to trigger any serious immunological reactions.
Hartley said they know they can produce huge quantities of these cousins for pennies a dose using yeast and bacteria methods.
"I can remember the day when we identified the first of the three molecules," Hartley said. "Just talking about it makes the hair stand up on my arm. It was a really big deal."
The team now hopes to attract funding to bring their compounds to pre-clinical testing and, hopefully, to full-scale human trials.
Hartley said safety is key.
"There have been clinical trials of microbicides that have been stopped and in fact there is some concern the microbicides did harm," Hartley said. "So we want to be extremely vigilant and look for any signs of toxicity before moving forward."
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