Logo image
Back
Piperidine CD4-mimetic compounds expose vulnerable Env epitopes sensitizing HIV-1-infected cells to ADCC
Journal article   Open access

Piperidine CD4-mimetic compounds expose vulnerable Env epitopes sensitizing HIV-1-infected cells to ADCC

Shilei Ding, William D Tolbert, Huile Zhu, Daniel Lee, Tyler Higgins, Xuchen Zhao, Dung Nguyen, Rebekah Sherburn, Jonathan Richard, Gabrielle-Gendron Lepage, …
bioRxiv : the preprint server for biology
24 Mar 2023
DOI: https://doi.org/10.1101/2023.03.23.533923
PMID: 36993184
url
https://doi.org/10.1101/2023.03.23.533923View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

The ability of 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 ( )-MCG-IV-210 sensitize HIV-1 infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, ( )-MCG-IV-210 derivatives, based on the piperidine scaffold which engage the gp120 within the Phe43 cavity by targeting the highly-conserved Asp Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit 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 Asp , 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 HIV-1-infected cells.

Metrics

24 Record Views

Details

Logo image