Purdue scientist receives NIH award to continue work on HIV/AIDS

August 25, 2011

WEST LAFAYETTE, Ind. - A Purdue University professor's research into treatments for drug-resistant HIV has earned him a prestigious National Institutes of Health award given to fewer than 5 percent of NIH-funded researchers.

Arun K. Ghosh

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Arun K. Ghosh, the Ian P. Rothwell Distinguished Professor of Chemistry and Medicinal Chemistry in the colleges of Science and Pharmacy, received a Method to Extend Research in Time - or MERIT - award from the National Institute of General Medical Sciences. The award can provide an extended grant cycle of up to 10 years and is intended to lessen the burden of grant application submission for researchers with a history of talent and success.

"The MERIT award is given to scientists whose productivity has been superior and who are expected to deliver creative, innovative research that will have an exceptional impact on the field," said Richard O. Buckius, Purdue's vice president for research. "It gives researchers the freedom to explore avenues that may be perceived as risky, in terms of being a sure success, but that could offer tremendous rewards in terms of people's health and the advancement of science. The award is a testament to the hard work of Professor Ghosh and the promise of his research into treatments for HIV and AIDS."

Ghosh created a molecule that in 2006 became the first approved by the Food and Drug Administration to treat drug-resistant HIV. The drug molecule, known as Darunavir, is now approved in 80 countries and is used as a frontline therapy for HIV and AIDS. Ghosh continues to improve upon his original success and designs even more powerful molecules in an effort to improve treatments and reduce side effects.

Historically HIV has frustrated drug developers because of its ability to develop resistance to treatment. Research shows that almost half of patients with HIV who initially respond to treatment develop drug-resistant strains within eight to 10 months. An additional 20 percent to 40 percent of patients have drug-resistant strains when they are first diagnosed, suggesting these strains can be transmitted from one person to the next, Ghosh said.

The virus develops resistance through mutations that change its structure and remove the point of interaction with a therapeutic molecule.

Ghosh targeted a viral enzyme critical for HIV replication and set out to design a way to block it from being used by the virus. Through analysis of X-ray structures of the enzyme protease, he identified a region of the enzyme that must be conserved for it to function and does not change significantly during mutation. Ghosh designed molecules to specifically interact with this portion of the enzyme's "backbone."

"Darunavir targets the region of the protease enzyme that must maintain its original structure in order for the virus to replicate," he said. "We designed a molecule to tightly bind to the conserved backbone of the enzyme, allowing the drug to maintain its effectiveness despite mutations."

Ghosh and his team also designed the molecule in such a way that it can easily and cost-effectively be mass-produced.

"Keeping the costs down greatly increases the accessibility of drugs to Third World countries where the epidemic is worst," he said. "We would like to see that our research alleviates suffering and helps as many people as possible."

The NIH owns the patent to Darunavir, and in 2010 provided a royalty-free license to the Medicines Patent Pool that makes it more affordable and accessible to people in developing countries.

Miles Fabian, the program director who oversees Ghosh's and other medicinal chemistry grants at the NIH's National Institute of General Medical Sciences, said Ghosh is precisely the type of investigator for which the MERIT Award program was instituted.

"It's hard to argue with success, and Professor Ghosh has been enormously successful in tackling HIV resistance to protease inhibitors," Fabian said. "He is clearly at an exceedingly productive phase in his career, and the latitude that comes with a MERIT Award will enable him to continue to make rapid progress toward developing next-generation medicines against drug-resistant HIV."

Ghosh continues to expand on the structural features of the molecule that make it so effective and is developing even more potent molecules to minimize the amount needed for treatment, which will reduce side effects. He recently created a molecule that is 10 times more potent against drug-resistant HIV than Darunavir. A paper detailing the work was published in the journal ChemMedChem.

"We've only scratched the surface of this area and there is much more to be done," Ghosh said. "In addition to improving HIV treatment, the backbone-binding concept behind this molecule could be applied to numerous other diseases, including yellow fever, Dengue virus and avian flu."

Ghosh and his team focus on structure-based molecular design. Through analysis of naturally occurring disease-inhibiting molecules, the team determines the key structural features involved. His team then optimizes the key features and eliminates any problematic features in a new synthetic molecule.

"The power of academic research relevant to human medicine is evolving and it is especially important as big pharmaceutical companies focus on more profitable areas like lifestyle drugs," Ghosh said. "Purdue is at the forefront of supporting academic drug discovery, and I have been fortunate to be at the right place at the right moment for nurturing my unconventional academic ideas."

Ghosh has had a long-term collaboration in this research with Hiroaki Mitsuya, chief and principal investigator for the Experimental Retrovirology Section at the National Cancer Institute.

The MERIT Award is given in recognition of exemplary research programs that have been continuously supported by the NIH for at least three cycles of funding and for which two concurrent competitive renewals receive a top score in their study section and require no revisions or amendments. The award provides five years of continued funding for a current project and the opportunity to extend the grant for an additional three to five years with only staff and council review, as opposed to having to submit a traditional competitive renewal application.

"I am very excited about the MERIT Award, and I look forward to taking our research to the next level," Ghosh said.

Writer:  Elizabeth K. Gardner, 765-494-2081, ekgardner@purdue.edu

Sources:   Arun Ghosh, 765-494-5323, akghosh@purdue.edu

                    Miles Fabian, 301-496-7301, fabianm@nigms.nih.gov

Related news release:

Research leads to first treatment for drug-resistant HIV