The overall program will use a combination of structural, chemical and biological tools to further the development of new and more effective drugs to combat AIDS. The five-year grant is being provided under the NIGMS initiative, Structural Biology of AIDS-Related Proteins.
Eddy Arnold, a resident faculty member of the Center for Advanced Biotechnology and Medicine (CABM) at Rutgers' Piscataway campus and a professor in Rutgers' department of chemistry and chemical biology, will serve as program director for the four projects. CABM is a research institute jointly administered by the University of Medicine and Dentistry of New Jersey (UMDNJ) and Rutgers.
"This major award enables Professor Arnold and his colleagues to continue their powerful work to develop effective treatments for this dreadful disease that threatens the well-being of millions of people worldwide," said Joseph J. Seneca, Rutgers' university vice president for academic affairs. "Rutgers is proud to have the work of its scientists recognized by this highly competitive award and to contribute to the improvement of public health through basic research."
Concurrent with his role as program director, Arnold will also function as principal investigator on one of the four projects, assisted by co-principal investigator Stefanos Sarafianos, an associate research professor at CABM. The other projects are led by Roger A. Jones, professor of chemistry and chemical biology at Rutgers and chair of the department; Stephen H. Hughes, a laboratory and section chief in the NIH National Cancer Institute's HIV Drug Resistance Program; and Michael A. Parniak, a professor of medicine in the Division of Infectious Diseases and in the department of molecular genetics and biochemistry at the University of Pittsburgh.
The projects employ structure-based drug design in their overall approach. This plan of attack requires the researchers to first identify proteins involved in spreading HIV through the body. X-ray crystallography is used to define the three-dimensional protein structure, which can then serve as a blueprint for scientists working to design an array of synthetic compounds to inhibit the protein's action. Through extensive testing and refinement, the array of compounds will be reduced down to one or more molecules that have highly specific activity and appear most effective in disabling the AIDS-related protein.
"The use of structure-based methodologies will improve the efficiency, enhance the accuracy and accelerate the process of drug design," said Aaron Shatkin, director of CABM. "It will open new opportunities for us to translate the results of biochemical research from bench top to bedside."
"The pharmaceutical industry has the capacity and expertise required to test all the molecules we design," Arnold said. "Then they can take the molecule that shows the greatest potential, systematically develop it into a drug and produce sufficient quantities for clinical testing. We are fortunate to have the opportunity to collaborate with creative scientists in industry because they can greatly leverage the value and the power of what we are doing."
Arnold's project is at the core of the fourfold research program. It concentrates on reverse transcriptase (RT), the protein used by the AIDS virus to replicate its genetic material. Drugs that inhibit the operation of RT have been effective in treating AIDS, but with the emergence of drug-resistant strains of the disease their effectiveness has been reduced. Arnold will use his laboratory's expertise in crystallography to reveal more details of how drug resistance comes about in RT. He will also generate structural information to be used in understanding how the RT molecule functions overall. Working with his three program collaborators, Arnold will pursue new ways to target RT and develop new inhibitors that can overcome drug resistance.
Since 1987, Hughes has collaborated with Arnold in the search for more effective AIDS therapies. Hughes has been particularly active in investigating the mechanisms of resistance to RT-inhibiting drugs, providing the biochemical analysis of the problem. In this project, Hughes will be engineering and producing RT variants for his own biochemical analyses and for Arnold's crystallography. Hughes, in collaboration with Arnold, will also engineer a series of RT molecules portraying different stages of activity, much like still frames in a motion picture. Arnold will use these to provide a further window through which to view RT and observe how it is operating and responding to the introduction of potential drug molecules.
Closely tied in to the work of the other collaborators, Jones will chemically synthesize specially modified DNA and RNA fragments to be used as tools in the investigation of drug resistance and inhibition mechanisms. Jones is making fragments that can be linked to various mutant forms of RT, enabling the team to identify and isolate specific functional segments of RT for further structural work by Arnold and biochemical analysis by Hughes and Parniak. Jones' innovative creations will allow specific molecules to be tracked as they interact with RT, permitting structural and biochemical studies not otherwise possible.
Parniak is making molecules that are related to another part of RT. In addition to its gene copying activity, RT acts like a pair of scissors, severing the original viral material while copies are being made. More than just housekeeping, this activity appears crucial to the virus's survival. Many drugs have been developed that work to inhibit the RT genetic function, but few have been identified for this secondary function. Parniak has developed some molecules that target this required activity. Disabling the virus in this novel way, he said, should offer yet another path for drug discovery.
021119-1
ArnoldNIGMSgrant.ed.wpd