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Publication Abstract from PubMed

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 beta(20-21) loop and the alpha(1)-helix lead to improved antiviral activity.

Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity.,Lee D, Niu L, Ding S, Zhu H, Tolbert WD, Medjahed H, Beaudoin-Bussieres G, Abrams C, Finzi A, Pazgier M, Smith AB 3rd ACS Med Chem Lett. 2024 Oct 28;15(11):1961-1969. doi: , 10.1021/acsmedchemlett.4c00403. eCollection 2024 Nov 14. PMID:39563795^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.