Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC

Shilei Ding, William D. Tolbert, Huile Zhu, Daniel Lee, Lorie Marchitto, Tyler Higgins, Xuchen Zhao, Dung Nguyen, Rebekah Sherburn, Jonathan Richard, Gabrielle Gendron-Lepage, Halima Medjahed, Mohammadjavad Mohammadi, Cameron Abrams, Marzena Pazgier*, Amos B. Smith*, Andrés Finzi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp368, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.

Original languageEnglish
Article number1185
Issue number5
StatePublished - May 2023
Externally publishedYes


  • HIV-1
  • Phe43 cavity
  • antibody-dependent cellular cytotoxicity (ADCC)
  • envelope glycoproteins
  • neutralization
  • small CD4 mimetic compounds (CD4mc)


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