Structural Evidence for Effectiveness of Darunavir and Two Related Antiviral Inhibitors against HIV-2 Protease

摘要

No drugs have been targeted specifically for HIV-2 infection despite the increasing prevalence worldwide. The antiviral HIV-1 protease inhibitor darunavir, and the chemically related GRL-98065 and GRL-06579A, were designed with the same chemical scaffold and different substituents at P2 and P2′ to optimize polar interactions for HIV-1 protease. These inhibitors are also effective antiviral agents for HIV-2 infected cells. Therefore, crystal structures of HIV-2 protease complexes with the three inhibitors have been solved at 1.2 Å resolution to analyze the molecular basis for their antiviral potency. Unusually, the crystals were grown in imidazole and zinc acetate buffer, which formed interactions with the protease and the inhibitors. Overall, the structures were very similar to the corresponding inhibitor complexes of HIV-1 protease with RMSD of 1.1 Å on main chain atoms. The majority of hydrogen bond and weaker C-H…O interactions with inhibitors were conserved in the HIV-2 and HIV-1 protease complexes, except for small changes in interactions with water or disordered side chains. Small differences were observed in the hydrophobic contacts for the darunavir complexes, which agreed with relative inhibition of the two proteases. These near-atomic resolution crystal structures verify the inhibitor potency for HIV-1 and HIV-2 proteases and will provide the basis for future development of antiviral inhibitors targeting HIV-2 protease.