Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Daniel Lee; Ling Niu; Shilei Ding; Huile Zhu; William D. Tolbert; Halima Medjahed; Guillaume Beaudoin-Bussières; Cameron Abrams; Andrés Finzi; Marzena Pazgier; Amos B. Smith

doi:10.1021/acsmedchemlett.4c00403

Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Daniel Lee, Ling Niu, Shilei Ding, Huile Zhu, William D. Tolbert, Halima Medjahed, Guillaume Beaudoin-Bussières, Cameron Abrams, Andrés Finzi^*, Marzena Pazgier^*, Amos B. Smith^*

^*Corresponding author for this work

Medicine

Research output: Contribution to journal › Article › peer-review

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 β_20-21 loop and the α₁-helix lead to improved antiviral activity.

Original language	English
Pages (from-to)	1961-1969
Number of pages	9
Journal	ACS Medicinal Chemistry Letters
Volume	15
Issue number	11
DOIs	https://doi.org/10.1021/acsmedchemlett.4c00403
State	Published - 14 Nov 2024

Keywords

Antibody-dependent cellular cytotoxicity (ADCC)
gp120
HIV
small molecule CD4 mimetic compounds (CD4mc)
structure−activity relationship (SAR)

Access to Document

10.1021/acsmedchemlett.4c00403

Cite this

Lee, D., Niu, L., Ding, S., Zhu, H., Tolbert, W. D., Medjahed, H., Beaudoin-Bussières, G., Abrams, C., Finzi, A., Pazgier, M., & Smith, A. B. (2024). Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity. ACS Medicinal Chemistry Letters, 15(11), 1961-1969. https://doi.org/10.1021/acsmedchemlett.4c00403

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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 β20-21 loop and the α1-helix lead to improved antiviral activity.",

keywords = "Antibody-dependent cellular cytotoxicity (ADCC), gp120, HIV, small molecule CD4 mimetic compounds (CD4mc), structure−activity relationship (SAR)",

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Lee, D, Niu, L, Ding, S, Zhu, H, Tolbert, WD, Medjahed, H, Beaudoin-Bussières, G, Abrams, C, Finzi, A, Pazgier, M & Smith, AB 2024, 'Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity', ACS Medicinal Chemistry Letters, vol. 15, no. 11, pp. 1961-1969. https://doi.org/10.1021/acsmedchemlett.4c00403

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AU - Tolbert, William D.

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AB - 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 β20-21 loop and the α1-helix lead to improved antiviral activity.

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