Multi-drug resistant (MDR) HIV continues to be a devastating problem for HIV/AIDS patients. Strains of HIV oftentimes confer resistance to drugs used in highly active antiretroviral therapy (HAART), rendering current therapies inadequate. In order to address this need, novel HIV-1 protease inhibitors can be designed that maintain potency against MDR strains of HIV. The structure-based design, asymmetric synthesis, biological evaluation, and X-ray crystallographic analysis of a novel class of HIV-1 protease inhibitors will be described. Utilizing the structural information gained from the X-ray crystal structure of FDA approved darunavir-bound wild type and mutant protease, highly active inhibitors were designed which maintained their potency across many MDR strains of HIV. Modifications were made to the P2 ligand in order to optimize the hydrogen bonding with the S2 pocket and flap region of the enzyme. Important hydrophobic contacts can also be made in the small S1-S2 subpocket. The hydrophobicity of the P1 ligand was also investigated. These inhibitors proved to be potent against HIV in enzymatic and antiviral assays. Selected inhibitors were tested against multi-drug resistant strains of HIV. High-resolution X-ray crystallography provided a structure of the inhibitor-bound protein which revealed key interactions in the active site of the enzyme. <br/>

Structure-based design, synthesis, biological evaluation, and x-ray crystallographic analysis of novel, highly potent HIV-1 protease inhibitors to address multi-drug resistant HIV

253rd National Meeting (2017)

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