Structural Analysis of Darunavir Analogs Against Primary Resistance Mutations in HIV Protease

Abstract

Antiretroviral therapies (ARTs) involve combinations of small molecule inhibitors that suppress the viral load of Human Immunodeficiency Virus (HIV), the causative agent of Acquired Immune Deficiency Symptom (AIDS). ARTs, currently the only defense against HIV, target critical proteins necessary for viral replication, such as HIV‐1 protease. The most potent FDA approved protease inhibitor, darunavir (DRV), is still susceptible to resistance if the protease acquires mutations in and around the active site. One method to avoid resistance is to optimize the inhibitor to fit the consensus volume that the protease's natural substrates occupy. Using this strategy, DRV analogs with larger moieties at the P1’ position were designed and synthesized to leverage unexploited space and create additional protease‐inhibitor interactions, resulting in inhibitors that are more potent and less susceptible to resistance. To elucidate the molecular mechanisms of active site resistance mutations against these inhibitors, we used a multidisciplinary approach, including biochemical assays and x‐ray crystallography. Results suggest that modifications to the DRV scaffold result in inhibitors with potency comparable to DRV, but structural analysis highlights differences in intermolecular and intramolecular interactions, which will inform future drug design.Support or Funding InformationThis work was supported in part by a grant from the National Institute of General Medical Sciences, National Institutes of Health (P01‐GM109767).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.