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

1 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), [1185]. https://doi.org/10.3390/v15051185

@article{ba9a37a042cb4e179cdc0e785061c1fc,

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 = "Funding Information: The authors are grateful to the donors who participated in this study. The authors thank the CRCHUM BSL3 and Flow Cytometry Platforms for technical assistance, and Mario Legault from the FRQS AIDS and Infectious Diseases network for cohort coordination and clinical samples. The use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and the contents of this publication are solely the responsibility of the authors. Funding Information: This work was supported by P01-GM56550/AI150741 to A.B.S., C.A., and A.F. This study was also supported by a Canadian Institutes of Health Research (CIHR) foundation grant #352417 to A.F. Funds were also provided by a CIHR team grant #422148 to A.F., a Canada Foundation for Innovation (CFI) grant #41027 to A.F., and by the National Institutes of Health to A.F. (R01 AI148379 and R01 AI150322), to M.P. and A.F. (R01 AI129769) and M.P. (AI116274), and (AI120756) to M.P. and Georgia Tomaras. This work was partially supported by 1UM1AI164562-01; co-funded by the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Neurological Disorders and Stroke; the National Institute on Drug Abuse; and the National Institute of Allergy and Infectious Diseases to A.F. A.F. is the recipient of a Canada Research Chair on Retroviral Entry #RCHS0235 950-232424. The funders had no role in the study{\textquoteright}s design, in the data collection and analysis, in the decision to publish, or in the preparation of the manuscript. Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = may,

doi = "10.3390/v15051185",

language = "English",

volume = "15",

journal = "Viruses",

issn = "1999-4915",

number = "5",

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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

N1 - Funding Information: The authors are grateful to the donors who participated in this study. The authors thank the CRCHUM BSL3 and Flow Cytometry Platforms for technical assistance, and Mario Legault from the FRQS AIDS and Infectious Diseases network for cohort coordination and clinical samples. The use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript, and the contents of this publication are solely the responsibility of the authors. Funding Information: This work was supported by P01-GM56550/AI150741 to A.B.S., C.A., and A.F. This study was also supported by a Canadian Institutes of Health Research (CIHR) foundation grant #352417 to A.F. Funds were also provided by a CIHR team grant #422148 to A.F., a Canada Foundation for Innovation (CFI) grant #41027 to A.F., and by the National Institutes of Health to A.F. (R01 AI148379 and R01 AI150322), to M.P. and A.F. (R01 AI129769) and M.P. (AI116274), and (AI120756) to M.P. and Georgia Tomaras. This work was partially supported by 1UM1AI164562-01; co-funded by the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute of Neurological Disorders and Stroke; the National Institute on Drug Abuse; and the National Institute of Allergy and Infectious Diseases to A.F. A.F. is the recipient of a Canada Research Chair on Retroviral Entry #RCHS0235 950-232424. The funders had no role in the study’s design, in the data collection and analysis, in the decision to publish, or in the preparation of the manuscript. Publisher Copyright: © 2023 by the authors.

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)

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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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