The goal of this project is to design new inhibitors of the CD4-gpl20 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. CD4 is known to bind gpl20 protein during HIV-1 entry and the major histocompatibility complex (MHC) class II protein during T cell activation important for both normal immune response and autoimmune disease and transplant rejection. Structural and mutational data reveal that different functions of CD4 (e.g. binding gpl20 versus MHC class II) are mediated by both overlapping and distinct sites on CD4. Therefore, the underlying hypothesis of our research is that small molecules targeting different surface pockets of CD4 proteins may have differential effects on gpl20 and MHC class II binding. The validity and feasibility of this hypothesis have been supported by our recent studies in which we have demonstrated that: (1) small molecule CD4 inhibitors can have significant biological activity in vitro and in vivo and be developed successfully for clinical trials in humans; and (2) two compounds HB01 and TJU103 targeting different CD4 surface pockets have selective inhibition of HIV-1 gpl20 and MHC class II binding, respectively. Here we propose to develop and apply new inhibitor design and screening strategies to generate highly potent and selective molecules as potential therapeutic agents for HIV-1 infection.
