Elucidation of the Emergence of HIV-1 Variants Resistant to HIV-1 Protease Dimerization Inhibitors (PDIs) and Development of Novel, Potent PDIs

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In this study period, we designed, synthesized and identified two HIV-1 protease inhibitors (PIs), GRL-1388 and GRL-1398, which contain a tetrahydropyrano-tetrahydrofuran moiety and exert potent activity against multi-drug resistant variants including DRV-resistant HIV-1 strains. We also identified GRL-0519, which contains an oxatricyclic-tetrahydrofuran and exerts potent anti-HIV activity against a wide spectrum of drug-resistant HIV-1s and potent activity to block the dimerization of HIV-1 protease monomers. Additionally, we identified a novel PI, GRL-0739, which contains cyclohexane-bis-THF, and GRL-09510, which persistently exerts potent antiviral activity against various multi-drug resistant clinical isolates and laboratory-generated highly PI-resistant variants.