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 journalArticlepeer-review

21 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 languageEnglish
Article numbere01325-19
JournalJournal of Virology
Volume93
Issue number24
DOIs
StatePublished - 1 Dec 2019
Externally publishedYes

Keywords

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

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