MANILA, Philippines - A team of researchers at the renowned Scripps Research Institute has discovered two new compounds that prove the existence of new binding sites on HIV protease.
Associate Professor C. David Stout, senior author of the study, said, “These results open the door to a whole new approach to drug design against HIV protease,” which is an enzyme used by HIV to create new, infectious viral particles.
Two members of the FightAIDS@Home team, research associate Alex Perryman, Ph.D., and professor Arthur Olson, were part of this innovative research, and are now hard at work to extend it.
This experimental breakthrough will serve as the basis for new drug development to combat the increasing number of drug-resistant HIV strains, as well as improve the potency of current drug therapies.
The findings appeared as the March cover story in the journal Chemical Biology and Drug Design.
According to the World Health Organization, about 33 million people currently suffer from HIV infections. Several drugs used to treat AIDS inhibit this HIV protease target, but drug-resistant mutants that impede the effectiveness of these drugs keep appearing and getting worse.
In a recent report from the US Centers for Disease Control and Prevention, the Philippines registered 143 HIV diagnoses in January 2010 alone. This is the highest one-month total recorded in the country.
The same report indicated that HIV diagnoses averaged about 60 each month in 2009, according to statistics released by the Department of Health (DOH). In December however, the number shot up to 126 cases.
With this rate, the number of people infected with HIV/AIDS in the Philippines can go up to 30,000 in three years time, according to a statement by Health Secretary Esperanza Cabral in a recent Reuters report.
“These are very alarming figures. IBM is trying to help out fight this global AIDS scare through the World Community Grid: FightAIDS@Home project,” said Andrea Escalona, country manager for marketing, communications and corporate citizenship and corporate affairs of IBM Philippines.
“Right now, almost 500,000 individuals in 80 countries have signed on (including me) to donate our idle computer time to the World Community Grid. We strongly encourage the rest of the PC users to donate their idle computer time for this effort,” she added.
Utilizing computing power from 1.5 million devices networked through IBM’s World Community Grid, the new sites on the HIV protease are being used as docking targets for virtual screening experiments, in order to guide the development of these chemical compounds into a new class of potent HIV inhibitors.
Using the massive computational resources of the World Community Grid, the FightAIDS@Home team has already docked over 500,000 compounds against these newly characterized binding sites.
By aggregating the unused cycle time of 1.5 million personal computers donated by volunteers in over 80 countries, World Community Grid is now the world’s largest public humanitarian grid, equivalent in power to a Top 10 supercomputer, and crunched more than 107,000 years of computational time in just five years for the Scripps Research Institute project, providing more than 104 million calculations.
“IBM’s World Community Grid and its volunteers help us run millions of computations to evaluate the potential interactions between compounds and mutant viral proteins,” said Olson, Anderson Research chairman professor of the Department of Molecular Biology at The Scripps Research Institute.
“Through this effort we were able to significantly speed up our investigation. Without the computational power of World Community Grid, it would have taken us many more years to get to this important step in our research,” he added.
Once the HIV virus enters a human cell, it uses a small set of proteins called enzymes to force the cell to produce many new copies of itself, which then go on to infect other cells. Most HIV drugs work by blocking the operation of one or more of these enzymes.
In the current work, the Scripps researchers are looking for new compounds that will stabilize the inhibited conformation, or shape, of the HIV protease enzyme, and thus help stop the virus from replicating.
Because HIV mutates so frequently, some drugs that inhibit the enzyme from replicating are no longer working, or are not working as effectively.
By running calculations on the World Community Grid FightAIDS@Home project, the team at Scripps is trying to develop new drugs that bind to more parts of the mutant enzyme, thereby shutting it down more effectively.
The World Community Grid speeds up humanitarian research by providing scientists with millions of dollars of supercomputer power, for free, that would otherwise not be available to them.
In a second paper recently published in the Journal of Molecular Biology, the Scripps team has used computational modeling to improve understanding of another HIV enzyme and key drug target — integrase.
Integrase, along with protease and a third enzyme, reverse-transcriptase, is one of three key proteins that allow the HIV virus to take over the cellular machinery of the host cell and replicate itself.
By producing a more accurate model of integrase, the research allows further searches for new drug molecules that will inhibit the mutant drug resistant forms of this enzyme, as well.
The Scripps team was recently awarded government stimulus funding as part of the American Recovery and Reinvestment Act to advance their new project against HIV integrase.