Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC

Shilei Ding; William D. Tolbert; Huile Zhu; Daniel Lee; Lorie Marchitto; Tyler Higgins; Xuchen Zhao; Dung Nguyen; Rebekah Sherburn; Jonathan Richard; Gabrielle Gendron-Lepage; Halima Medjahed; Mohammadjavad Mohammadi; Cameron Abrams; Marzena Pazgier; Amos B. Smith; Andrés Finzi

doi:10.3390/v15051185

Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC

Shilei Ding, William D. Tolbert, Huile Zhu, Daniel Lee, Lorie Marchitto, Tyler Higgins, Xuchen Zhao, Dung Nguyen, Rebekah Sherburn, Jonathan Richard, Gabrielle Gendron-Lepage, Halima Medjahed, Mohammadjavad Mohammadi, Cameron Abrams, Marzena Pazgier^*, Amos B. Smith^*, Andrés Finzi^*

^*Corresponding author for this work

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

6 Scopus citations

Abstract

The ability of the 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 (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp³⁶⁸ Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the 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 Asp³⁶⁸, 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 of HIV-1-infected cells.

Original language	English
Article number	1185
Journal	Viruses
Volume	15
Issue number	5
DOIs	https://doi.org/10.3390/v15051185
State	Published - May 2023
Externally published	Yes

Keywords

HIV-1
Phe43 cavity
antibody-dependent cellular cytotoxicity (ADCC)
envelope glycoproteins
neutralization
small CD4 mimetic compounds (CD4mc)

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10.3390/v15051185

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Ding, S., Tolbert, W. D., Zhu, H., Lee, D., Marchitto, L., Higgins, T., Zhao, X., Nguyen, D., Sherburn, R., Richard, J., Gendron-Lepage, G., Medjahed, H., Mohammadi, M., Abrams, C., Pazgier, M., Smith, A. B., & Finzi, A. (2023). Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC. Viruses, 15(5), Article 1185. https://doi.org/10.3390/v15051185

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title = "Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC",

abstract = "The ability of the 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 (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the 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 Asp368, 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 of HIV-1-infected cells.",

keywords = "HIV-1, Phe43 cavity, antibody-dependent cellular cytotoxicity (ADCC), envelope glycoproteins, neutralization, small CD4 mimetic compounds (CD4mc)",

author = "Shilei Ding and Tolbert, {William D.} and Huile Zhu and Daniel Lee and Lorie Marchitto and Tyler Higgins and Xuchen Zhao and Dung Nguyen and Rebekah Sherburn and Jonathan Richard and Gabrielle Gendron-Lepage and Halima Medjahed and Mohammadjavad Mohammadi and Cameron Abrams and Marzena Pazgier and Smith, {Amos B.} and Andr{\'e}s Finzi",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

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doi = "10.3390/v15051185",

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Ding, S, Tolbert, WD, Zhu, H, Lee, D, Marchitto, L, Higgins, T, Zhao, X, Nguyen, D, Sherburn, R, Richard, J, Gendron-Lepage, G, Medjahed, H, Mohammadi, M, Abrams, C, Pazgier, M, Smith, AB & Finzi, A 2023, 'Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC', Viruses, vol. 15, no. 5, 1185. https://doi.org/10.3390/v15051185

TY - JOUR

T1 - Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC

AU - Ding, Shilei

AU - Tolbert, William D.

AU - Zhu, Huile

AU - Lee, Daniel

AU - Marchitto, Lorie

AU - Higgins, Tyler

AU - Zhao, Xuchen

AU - Nguyen, Dung

AU - Sherburn, Rebekah

AU - Richard, Jonathan

AU - Gendron-Lepage, Gabrielle

AU - Medjahed, Halima

AU - Mohammadi, Mohammadjavad

AU - Abrams, Cameron

AU - Pazgier, Marzena

AU - Smith, Amos B.

AU - Finzi, Andrés

PY - 2023/5

Y1 - 2023/5

N2 - The ability of the 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 (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the 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 Asp368, 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 of HIV-1-infected cells.

AB - The ability of the 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 (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the 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 Asp368, 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 of HIV-1-infected cells.

KW - HIV-1

KW - Phe43 cavity

KW - antibody-dependent cellular cytotoxicity (ADCC)

KW - envelope glycoproteins

KW - neutralization

KW - small CD4 mimetic compounds (CD4mc)

UR - http://www.scopus.com/inward/record.url?scp=85160622266&partnerID=8YFLogxK

U2 - 10.3390/v15051185

DO - 10.3390/v15051185

M3 - Article

AN - SCOPUS:85160622266

SN - 1999-4915

VL - 15

JO - Viruses

JF - Viruses

IS - 5

M1 - 1185

ER -

Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC

Abstract

Keywords

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