Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120

Navid Madani, Arne Schön, Amy M. Princiotto, Judith M. LaLonde, Joel R. Courter, Takahiro Soeta, Danny Ng, Liping Wang, Evan T. Brower, Shi Hua Xiang, Young Do Kwon, Chih chin Huang, Richard Wyatt, Peter D. Kwong, Ernesto Freire, Amos B. Smith, Joseph Sodroski

Research output: Contribution to journalArticle

134 Scopus citations

Abstract

Human immunodeficiency virus (HIV-1) interaction with the primary receptor, CD4, induces conformational changes in the viral envelope glycoproteins that allow binding to the CCR5 second receptor and virus entry into the host cell. The small molecule NBD-556 mimics CD4 by binding the gp120 exterior envelope glycoprotein, moderately inhibiting virus entry into CD4-expressing target cells and enhancing CCR5 binding and virus entry into CCR5-expressing cells lacking CD4. Studies of NBD-556 analogs and gp120 mutants suggest that (1) NBD-556 binds within the Phe 43 cavity, a highly conserved, functionally important pocket formed as gp120 assumes the CD4-bound conformation; (2) the NBD-556 phenyl ring projects into the Phe 43 cavity; (3) enhancement of CD4-independent infection by NBD-556 requires the induction of conformational changes in gp120; and (4) increased affinity of NBD-556 analogs for gp120 improves antiviral potency during infection of CD4-expressing cells.

Original languageEnglish (US)
Pages (from-to)1689-1701
Number of pages13
JournalStructure
Volume16
Issue number11
DOIs
StatePublished - Nov 12 2008

Keywords

  • MICROBIO
  • MOLIMMUNO
  • PROTEINS

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Madani, N., Schön, A., Princiotto, A. M., LaLonde, J. M., Courter, J. R., Soeta, T., Ng, D., Wang, L., Brower, E. T., Xiang, S. H., Do Kwon, Y., Huang, C. C., Wyatt, R., Kwong, P. D., Freire, E., Smith, A. B., & Sodroski, J. (2008). Small-Molecule CD4 Mimics Interact with a Highly Conserved Pocket on HIV-1 gp120. Structure, 16(11), 1689-1701. https://doi.org/10.1016/j.str.2008.09.005