Study of generation and dynamics of HIV enzymes essential for replication and structural design of their inhibitors

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We reported in this study period that, through superinfection of cells with multiple HIV-1 strains and homologous recombination, HIV-1 can acquire high-level resistance against darunavir (DRV), to which HIV-1 hardly acquires resistance. We also identified cyclopentanyl-tetrahydrofuran-containing GRL-02031, which binds to HIV-1 protease in a bimodal way and exerts potent antiviral activity. Furthermore, we obtained GRL-0216A and -0286A with a macrocyclic ligand plus GRL-1388A and -1398A which contain a tetrahydropyrano-tetrahydrofuran moiety and exert potenta activity agaisnt multi-drug resistant varinats including DRV-resistant HIV-1 strains. We also ideintified GRL-0519A, which contains an oxatricyclic-tetrahydrofuran with potent anti-HIV activtiy agaisnt a wide spectrum of drug-resistant HIV-1s and potent activity to block the dimerization of HIV-1 portease monomers.