HIV-1 Integrase Structure and Function as a Therapeutic Target

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DESCRIPTION (provided by candidate): The candidate's main objective is to establish a vigorous, independent research program centered on structure and function studies of HIV replication complexes. The new findings will be exploited to discover novel effective antiretroviral inhibitors. Since August of 2003 the candidate has been Assistant Professor at the Ohio State University (OSU) College of Pharmacy. The candidate's research is currently supported by the following two NIH grants: R01 - "structural studies of HIV-1 integration" and R21 - "HIV-1 Gag structure as a therapeutic target". An Independent Scientist Award (ISA) at this stage of the candidate's career would help him enormously to focus on his research endeavors. The candidate's teaching load for the current academic year includes instructing undergraduate, professional and graduate students 60 lectures and 120 hrs laboratory courses. These very significant teaching responsibilities slow down the candidate's research activities. If awarded an ISA, the University will reduce the candidate's teaching load to an -15% effort level. The candidate's research program would benefit greatly from this reduced course load. He would have time to pursue the lab work himself and directly supervise his postdoctoral fellow and graduate students. The candidate would attend scientific meetings and workshops to enhance his knowledge in the areas that he plans to pursue in future and more closely interact with other scientists in the field. The facilities and research environment at OSU are also conducive to the stated goals. The candidate's current research activities aim to elucidate how HIV-1 IN interacts with cognate nucleic acids and cellular cofactors, and identify new small molecules inhibiting these functionally essential interactions. HIV-1 IN is commonly viewed as an important therapeutic target for the following reasons: catalytic activities of IN are required for viral replication, there is no closely related cellular equivalent of IN, and specific IN inhibitors are likely to be effective against viral strains resistant to currently available therapies targeting reverse transcriptase, protease, and fusion. Detailed structural and mechanistic information on functional HIV-1 IN nucleoprotein complexes could aid drug design efforts. The candidate's research group is addressing these important problems using innovative biochemical/biophysical approaches including mass spectrometric protein footprinting technologies developed in the candidate's laboratory.