W0049

High Resolution Crystal Structures of HIV-1 Protease Mutants With Potent New Inhibitors. Yunfeng Tie¹, Peter Boross^2,3, Yuan-Fang Wang³, Patra Volarath¹, Laquasha Gaddis³, Geoffrey Bilcer⁴, Arun K. Ghosh⁴, John M. Louis⁵, Robert W. Harrison^1,6, Irene T. Weber^1,3, ¹Dept. of Chemistry, Georgia State Univ., Atlanta, GA; ²Dept. of Biochemistry and Molecular Biology, Faculty of Medicine, Univ. of Debrecen, Hungary; ³Dept. of Biology, Georgia State Univ., Atlanta, GA; ⁴Dept. of Chemistry, Univ. of Illinois at Chicago, Chicago, IL; ⁵Laboratory of Chemical Physics, National Inst. of Diabetes and Digestive and Kidney Diseases, The National Institutes of Health, Bethesda, MD, and ⁶Dept. of Computer Science, Georgia State Univ., Atlanta, GA.

Atomic resolution structures of the HIV protease with new designed non-peptide inhibitors are described. Most of the problems associated with the HIV therapy, such as rapid development of drug-resistant variants and side effects of drugs, are consequences of the necessarily long-term use of the drugs. The new inhibitors have high potency and excellent resistance profile. They are designed to induce tighter inhibitor interactions with the protease, and thus reduce the resistance caused by mutation. By these high resolution structures (1.6 to 1.1 Å), we will be able to understand the molecular basis for the protein-inhibitor interaction, prove whether the inhibitor design goal has been met and guide the design of potential drugs. Also, the inhibitors have been studied with frequently observed resistant mutants of HIV-1 protease, including V82A and I84V, in order to define any structural changes associated with mutations. The new crystal structures will be important for the design of the next generation of HIV protease inhibitors which will more effectively target resistant virus. (Research supported in part by NIH grants GM62920, GM53386 and OTKA F35191).