HIV-1 protease inhibitors are vital members of highly-active antiretroviral therapy (HAART). Upon the introduction of HAART, the mortality and morbidity rate for HIV/AIDS patients receiving HAART therapy has substantially decreased. Still, the emergence of multi-drug resistant (MDR) strains of HIV often renders current therapies inadequate. The design of novel, highly potent HIV-1 protease inhibitors is necessary to address the MDR viral issue. The design, synthesis, and biological evaluation of novel classes of HIV-1 protease inhibitors will be discussed. Utilizing the structural information gained from the X-ray crystal structure of FDA approved darunavir-bound wild type and mutant protease, highly active inhibitors were designed. Design strategies are focused on the optimization of the non-prime side of the active site. Hydrogen bonding interactions can be optimized, particularly in the S2 subsite of the active site. Modulation of the P1 hydrophobic ligand indicates an expanded hydrophobic space in the S1 subsite. Furthermore, the optimization of van der Waals interactions in the S1-S2 subsites resulted in exceedingly potent inhibitors. Inhibitors of all classes proved to be potent against HIV in enzymatic and antiviral assays. Selected inhibitors were tested further against multi-drug resistant HIV. X-ray crystallographic elucidation of an inhibitor-enzyme co-crystal provided structural information into the binding mode of each inhibitor class.

Novel HIV-1 protease inhibitors: Design, synthesis, and biological evaluation

254th National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.