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Published, Version of Record (VoR)Open Access (License Unspecified), Open
Journal article
Piperidine CD4-mimetic compounds expose vulnerable Env epitopes sensitizing HIV-1-infected cells to ADCC
bioRxiv : the preprint server for biology
24 Mar 2023
PMID: 36993184
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.
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Details
- Title
- Piperidine CD4-mimetic compounds expose vulnerable Env epitopes sensitizing HIV-1-infected cells to ADCC
- Creators
- Shilei Ding - CRCHUM;William D Tolbert - Institute of Human VirologyHuile Zhu - California University of PennsylvaniaDaniel Lee - California University of PennsylvaniaTyler Higgins - California University of PennsylvaniaXuchen Zhao - California University of PennsylvaniaDung Nguyen - Uniformed Services University of the Health SciencesRebekah Sherburn - Uniformed Services University of the Health SciencesJonathan Richard - Centre Hospitalier de l’Université de MontréalGabrielle-Gendron LepageHalima Medjahed - CRCHUM;Mohammadjavad Mohammadi - Drexel UniversityCameron Abrams - Drexel UniversityMarzena Pazgier - Uniformed Services University of the Health SciencesAmos B Smith - California University of PennsylvaniaAndrés Finzi - CRCHUM;
- Publication Details
- bioRxiv : the preprint server for biology
- Publisher
- American Physical Society (APS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Other Identifier
- 991020336744104721