The goal of this project is to design new inhibitors of the CD4-gpl2O complex critical for the entry of human immunodeficiency virus type 1 (HIV-1). In addition, we intend to use this project as a model to develop a general structure-based approach to discover small molecule inhibitors of protein-protein interactions involved in virus entry process. The underlying hypothesis of our research is that inhibitors targeting specific surface pockets of CD4 and/or gp120 proteins may disrupt their interaction and thus could be used as effective anti-HIV agents. Exploiting the recent crystal structure of the gp120-CD4 complex determined by our collaborator, we will carry out theoretical and experimental studies to identify potential ligands of protein surface pockets within the interface. In preliminary studies, we have discovered a small molecule ligand of a CN surface pocket, HBO1. We have demonstrated that HBO1 selectively blocked gpl2O binding and M- and T-tropic HIV-1 viral entry, but meanwhile did not affect MHC class II binding for normal immune response. Here we propose to apply an interdisciplinary approach to study the structure-activity relationship of HBO 1 in order to develop a new generation of potent and selective analogs as potential therapeutic agents for HIV infection.
