It is necessary to understand the molecular basis for the action of HIV protease and its inhibitor-resistant variants in order to develop new inhibitors and new therapeutic strategies. Previously, the comparison of the crystal structures and specificities of two distinctly different retroviral proteases from HIV and Rous sarcoma virus (RSV) were used to identify important inhibitor-protease interactions and the protease residues that are critical for recognition of substrates. These key residues were predicted to occur in the inhibitor-resistant variants of HIV protease, and are the most commonly mutated residues in the known resistant variants. Variants of both HIV-1 and RSV proteases will be studied in order to model the development of resistance to inhibitors. The crystals structures of these variant proteins will be determined, their specificities for peptide substrates representing the natural polyprotein cleavage sites will be measured, and their effects on viral replication will be studied. New inhibitors will be evaluated for their ability to inhibit HIV protease variants and for their antiviral effects. Computational methods have been developed that predict the relative efficiency of peptide substrates of HIV protease. These calculations will be used to predict the effects of the resistant mutants on cleavage of the polyproteins and viral replication and the activity of different inhibitors. One major advantage is that these predictions will be applicable to any newly discovered resistant mutants of HIV protease, and will help to design new inhibitors to overcome resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI041380-01A1
Application #
2429532
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1997-07-01
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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