Journal article
Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity
ACS medicinal chemistry letters, v 15(11), pp 1961-1969
14 Nov 2024
PMID: 39563795
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity
- Creators
- Daniel Lee - University of PennsylvaniaLing Niu - Uniformed Services University of the Health SciencesShilei Ding - Centre Hospitalier de l’Université de MontréalHuile Zhu - California University of PennsylvaniaWilliam D. Tolbert - Uniformed Services University of the Health SciencesHalima Medjahed - Centre Hospitalier de l’Université de MontréalGuillaume Beaudoin-Bussieres - Centre Hospitalier de l’Université de MontréalCameron Abrams - Drexel University, Chemical and Biological EngineeringAndres Finzi - Centre Hospitalier de l’Université de MontréalMarzena Pazgier - Uniformed Services University of the Health SciencesAmos B. Smith III - University of Pennsylvania
- Publication Details
- ACS medicinal chemistry letters, v 15(11), pp 1961-1969
- Publisher
- Amer Chemical Soc
- Number of pages
- 9
- Grant note
- 41027 / Canada Foundation for Innovation (CFI); Canada Foundation for Innovation 422148 / CIHR Team grant; Canadian Institutes of Health Research (CIHR) R01 AI148379; R01 AI150322; R01AI176531; AI174908; P01AI162242 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:001344008900001
- Scopus ID
- 2-s2.0-85207782903
- Other Identifier
- 991021933315504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal