Article

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

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, JFB 824, Boston, MA 02115, USA.
Structure (Impact Factor: 6.79). 12/2008; 16(11):1689-701. DOI: 10.1016/j.str.2008.09.005
Source: PubMed

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.

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Available from: Arne Schon, Apr 25, 2014
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    • "Binding CD4 creates the " Phe 43 cavity " , an interfacial cavity bounded by all three gp120 domains and by phenylalanine 43 of CD4. The walls of the Phe 43 cavity are lined by well-conserved gp120 residues, rendering it suitable as a target for small-molecule inhibitors (Madani et al., 2008). Interventional approaches targeting the CD4-binding site, using either antibodies or small molecules, would benefit from a better understanding of the conformational transitions involved in receptor binding. "
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