Structure-activity and resistance studies of HIV-1 protease inhibitors

Abstract: The present investigation was undertaken in order to identify inhibitors of HIV-1 protease that would be efficient in vivo and against HIV-1 protease carrying mutations known to confer resistance to inhibitors in clinical use. A second interest was to understand details of inhibitory mechanisms and to gain understanding of the molecular details of resistance.Linear inhibitors of transition-state type showed to have a resistance pattern similar to protease inhibitors in clinical use, whereas cyclic inhibitors of sulfonamide were somewhat different in their inhibitory profiles. It was found that mutation L90M in some situations could lessen the decrease in overall efficiency suffered by the enzyme when aquiring other mutations. Also presented are results from the characterization of double mutation I84V/L90M, formerly not investigated. Testing of triple and quadruple mutant confirmed the additive features of some mutations. In an attempt to find new leads for inhibitor development, extracts from bee propolis, a natural product, was investigated, and it was found that one extract inhibited wild-type enzyme with an I50-value of 0.2 μg/mL. Even more interesting is the result that propolis extract also inhibited all the investigated mutant enzymes.