STRUCTURAL STUDIES OF INHIBITOR COMPLEXES OF HIV-1 PROTEASE AND OF ITS DRUG RESISTANCE MUTANTS. T.N. Bhat, R.S. Randad, A.Y. Lee, L. Lubkowska, S. Munshi, B. Yu, S. Gulnik, P.J. Collins, J.W. Erickson, Structural Biochemistry Program, Frederick Biomedical Supercomputing Center, SAIC, National Cancer Institute-Frederick, Cancer Research and Development Center, Frederick, Maryland, 21702-1201

HIV-1 protease is essential for the maturation of fully infectious virions and it is an important target for the design of antiviral therapeutic agents for AIDS. We have studied the crystal structures of numerous inhibitors complexed with the HIV-1 protease some of which are currently undergoing clinical trials. We have used these crystal structures to develop our understanding of the critical features of binding that contribute to potency. A major obstacle to antiviral therapy for HIV has been the emergence of drug resistance mutations in HIV-1 protease. To understand the structural basis of drug resistance, studies were undertaken to determine the crystal structures of mutants of HIV-1 protease complexed with various inhibitors. These structural studies reveal unexpected conformational rearrangements of protein and inhibitor molecules. The changes observed in mutant complexes underscore the significance of flexibility of both the enzyme and inhibitor molecules for understanding resistance mechanisms and for designing second generation inhibitors.