Optimization\nof a Piperidine CD4-Mimetic Scaffold\nSensitizing HIV‑1 Infected Cells to Antibody-Dependent Cellular\nCytotoxicity

The ability of the HIV-1 accessory proteins Nef and Vpu\nto decrease\nCD4 protects infected cells from antibody-dependent cellular cytotoxicity\n(ADCC) by limiting the exposure of vulnerable epitopes to envelope\nglycoprotein (Env). Small-molecule CD4 mimetics (CD4mcs) based on\npiperidine scaffolds represent a new family of agents capable of sensitizing\nHIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes\non Env that are recognized by non-neutralizing antibodies which are\nabundant in plasma of people living with HIV. Here, we employed the\ncombined methods of parallel synthesis, structure-based design, and\noptimization to generate a new line of piperidine-based CD4mcs, which\nsensitize HIV-1 infected cells to ADCC activity. The X-ray crystallographic\nstudy of the CD4mcs within the gp120 residues suggests that the positioning\nof the CD4mc inside the Phe43 cavity and synergistic contact of the\nCD4mc with the β<sub>20–21</sub> loop and the α<sub>1</sub>-helix lead to improved antiviral activity.