The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 protects infected cells from antibody-dependent cellular cytotoxicity (ADCC) by limiting the exposure of vulnerable epitopes to envelope glycoprotein (Env). Small-molecule CD4 mimetics (CD4mcs) based on piperidine scaffolds represent a new family of agents capable of sensitizing HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes on Env that are recognized by non-neutralizing antibodies which are abundant in plasma of people living with HIV. Here, we employed the combined methods of parallel synthesis, structure-based design, and optimization to generate a new line of piperidine-based CD4mcs, which sensitize HIV-1 infected cells to ADCC activity. The X-ray crystallographic study of the CD4mcs within the gp120 residues suggests that the positioning of the CD4mc inside the Phe43 cavity and synergistic contact of the CD4mc with the β loop and the α-helix lead to improved antiviral activity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571091 | PMC |
http://dx.doi.org/10.1021/acsmedchemlett.4c00403 | DOI Listing |
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