Currently approved HIV-1 protease inhibitors are prone to drug resistance due to the rapid evolution of HIV. Darunavir (DRV) has shown great promise in the treatment of drug resistant HIV, but emerging resistance strains are challenging its efficacy. We have developed a substrate envelope guided strategy to rationally design HIV-1 protease inhibitors with improved potency and resistance profiles. This strategy together with insights from detailed structural analysis of protease-inhibitor complexes led to the design of new inhibitors with high potency against highly resistant strains of HIV. Here, we describe the substrate envelope guided design, synthesis, biological evaluation, and X-ray crystal structure analysis of a series of novel HIV-1 protease inhibitors. The inhibitors were designed by incorporating key features of DRV and other FDA approved HIV-1 protease inhibitors with variable P1, P1' and P2' moieties. The SAR data and molecular insights from X-ray crystal structures may allow further optimization of this novel series of HIV-1 protease inhibitors.

Structure-based design, synthesis, evaluation and x-ray crystal structure analysis of HIV-1 protease inhibitors with modified P1, P1’and P2’ groups

256th National Meeting (2018)

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