Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity
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 β<sub>20-21</sub> loop and the α<sub>1</sub>-helix lead to improved antiviral activity.
Authors
- Guillaume Beaudoin-Bussières (ORCID: https://orcid.org/0000-0002-8092-4101)
- Cameron F. Abrams (ORCID: https://orcid.org/0000-0002-1240-0816)
- Marzena Pazgier (ORCID: https://orcid.org/0000-0003-0594-5057)
- William D. Tolbert (ORCID: https://orcid.org/0000-0001-7549-9596)
- Amos B. Smith (ORCID: https://orcid.org/0000-0002-1712-8567)
- Huile Zhu
- Halima Medjahed
- Daniel Lee (ORCID: https://orcid.org/0000-0003-0476-9135)
- Shilei Ding (ORCID: https://orcid.org/0000-0003-1895-5131)
- Ling Niu (ORCID: https://orcid.org/0000-0002-2702-0779)
- Andrés Finzi
Institutions
- Uniformed Services University of the Health Sciences (US)
- Centre Hospitalier de l’Université de Montréal (CA)
- Université de Montréal (CA)
- Drexel University (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00403
- Citations
- 2
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.59
Funders
- University of Pennsylvania
- Canada Foundation for Innovation
- National Institutes of Health
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé