A new family of small-molecule cd4-mimetic compounds contacts highly conserved aspartic acid 368 of HIV-1 gp120 and mediates antibody-dependent cellular cytotoxicity

Shilei Ding; Melissa C. Grenier; William D. Tolbert; Dani Vézina; Rebekah Sherburn; Jonathan Richard; Jérémie Prévost; Jean Philippe Chapleau; Gabrielle Gendron-Lepage; Halima Medjahed; Cameron Abrams; Joseph Sodroski; Marzena Pazgier; Amos B. Smith; Andrés Finzi

doi:10.1128/JVI.01325-19

A new family of small-molecule cd4-mimetic compounds contacts highly conserved aspartic acid 368 of HIV-1 gp120 and mediates antibody-dependent cellular cytotoxicity

Shilei Ding, Melissa C. Grenier, William D. Tolbert, Dani Vézina, Rebekah Sherburn, Jonathan Richard, Jérémie Prévost, Jean Philippe Chapleau, Gabrielle Gendron-Lepage, Halima Medjahed, Cameron Abrams, Joseph Sodroski, Marzena Pazgier, Amos B. Smith, Andrés Finzi^*

^*Corresponding author for this work

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

23 Scopus citations

Abstract

The HIV-1 envelope glycoprotein (Env) trimer mediates virus entry into cells. The "closed" conformation of Env is resistant to nonneutralizing antibodies (nnAbs). These antibodies mostly recognize occluded epitopes that can be exposed upon binding of CD4 or small-molecule CD4 mimetics (CD4mc). Here, we describe a new family of small molecules that expose Env to nnAbs and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC). These compounds have a limited capacity to inhibit virus infection directly but are able to sensitize viral particles to neutralization by otherwise nonneutralizing antibodies. Structural analysis shows that some analogs of this family of CD4mc engage the gp120 Phe43 cavity by contacting the highly conserved D368 residue, making them attractive scaffolds for drug development.

Original language	English
Article number	e01325-19
Journal	Journal of Virology
Volume	93
Issue number	24
DOIs	https://doi.org/10.1128/JVI.01325-19
State	Published - 1 Dec 2019
Externally published	Yes

Keywords

ADCC
CD4 mimetics
Env
Envelope glycoproteins
HIV-1
Neutralization
Small-molecule inhibitors

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10.1128/JVI.01325-19

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Ding, S., Grenier, M. C., Tolbert, W. D., Vézina, D., Sherburn, R., Richard, J., Prévost, J., Chapleau, J. P., Gendron-Lepage, G., Medjahed, H., Abrams, C., Sodroski, J., Pazgier, M., Smith, A. B., & Finzi, A. (2019). A new family of small-molecule cd4-mimetic compounds contacts highly conserved aspartic acid 368 of HIV-1 gp120 and mediates antibody-dependent cellular cytotoxicity. Journal of Virology, 93(24), Article e01325-19. https://doi.org/10.1128/JVI.01325-19

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title = "A new family of small-molecule cd4-mimetic compounds contacts highly conserved aspartic acid 368 of HIV-1 gp120 and mediates antibody-dependent cellular cytotoxicity",

abstract = "The HIV-1 envelope glycoprotein (Env) trimer mediates virus entry into cells. The {"}closed{"} conformation of Env is resistant to nonneutralizing antibodies (nnAbs). These antibodies mostly recognize occluded epitopes that can be exposed upon binding of CD4 or small-molecule CD4 mimetics (CD4mc). Here, we describe a new family of small molecules that expose Env to nnAbs and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC). These compounds have a limited capacity to inhibit virus infection directly but are able to sensitize viral particles to neutralization by otherwise nonneutralizing antibodies. Structural analysis shows that some analogs of this family of CD4mc engage the gp120 Phe43 cavity by contacting the highly conserved D368 residue, making them attractive scaffolds for drug development.",

keywords = "ADCC, CD4 mimetics, Env, Envelope glycoproteins, HIV-1, Neutralization, Small-molecule inhibitors",

author = "Shilei Ding and Grenier, {Melissa C.} and Tolbert, {William D.} and Dani V{\'e}zina and Rebekah Sherburn and Jonathan Richard and J{\'e}r{\'e}mie Pr{\'e}vost and Chapleau, {Jean Philippe} and Gabrielle Gendron-Lepage and Halima Medjahed and Cameron Abrams and Joseph Sodroski and Marzena Pazgier and Smith, {Amos B.} and Andr{\'e}s Finzi",

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Ding, S, Grenier, MC, Tolbert, WD, Vézina, D, Sherburn, R, Richard, J, Prévost, J, Chapleau, JP, Gendron-Lepage, G, Medjahed, H, Abrams, C, Sodroski, J, Pazgier, M, Smith, AB & Finzi, A 2019, 'A new family of small-molecule cd4-mimetic compounds contacts highly conserved aspartic acid 368 of HIV-1 gp120 and mediates antibody-dependent cellular cytotoxicity', Journal of Virology, vol. 93, no. 24, e01325-19. https://doi.org/10.1128/JVI.01325-19

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T1 - A new family of small-molecule cd4-mimetic compounds contacts highly conserved aspartic acid 368 of HIV-1 gp120 and mediates antibody-dependent cellular cytotoxicity

AU - Ding, Shilei

AU - Grenier, Melissa C.

AU - Tolbert, William D.

AU - Vézina, Dani

AU - Sherburn, Rebekah

AU - Richard, Jonathan

AU - Prévost, Jérémie

AU - Chapleau, Jean Philippe

AU - Gendron-Lepage, Gabrielle

AU - Medjahed, Halima

AU - Abrams, Cameron

AU - Sodroski, Joseph

AU - Pazgier, Marzena

AU - Smith, Amos B.

AU - Finzi, Andrés

PY - 2019/12/1

Y1 - 2019/12/1

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AB - The HIV-1 envelope glycoprotein (Env) trimer mediates virus entry into cells. The "closed" conformation of Env is resistant to nonneutralizing antibodies (nnAbs). These antibodies mostly recognize occluded epitopes that can be exposed upon binding of CD4 or small-molecule CD4 mimetics (CD4mc). Here, we describe a new family of small molecules that expose Env to nnAbs and sensitize infected cells to antibody-dependent cellular cytotoxicity (ADCC). These compounds have a limited capacity to inhibit virus infection directly but are able to sensitize viral particles to neutralization by otherwise nonneutralizing antibodies. Structural analysis shows that some analogs of this family of CD4mc engage the gp120 Phe43 cavity by contacting the highly conserved D368 residue, making them attractive scaffolds for drug development.

KW - ADCC

KW - CD4 mimetics

KW - Env

KW - Envelope glycoproteins

KW - HIV-1

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ER -

A new family of small-molecule cd4-mimetic compounds contacts highly conserved aspartic acid 368 of HIV-1 gp120 and mediates antibody-dependent cellular cytotoxicity

Abstract

Keywords

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