A synthetic CD4-heparan sulfate glycoconjugate inhibits CCR5 and CXCR4 HIV-1 attachment and entry

Françoise Baleux; Latino Loureiro-Morais; Yael Hersant; Pascal Clayette; Fernando Arenzana-Seisdedos; David Bonnaffé; Hugues Lortat-Jacob

doi:10.1038/nchembio.207

A synthetic CD4-heparan sulfate glycoconjugate inhibits CCR5 and CXCR4 HIV-1 attachment and entry

Nat Chem Biol. 2009 Oct;5(10):743-8. doi: 10.1038/nchembio.207. Epub 2009 Sep 6.

Authors

Françoise Baleux¹, Latino Loureiro-Morais, Yael Hersant, Pascal Clayette, Fernando Arenzana-Seisdedos, David Bonnaffé, Hugues Lortat-Jacob

Affiliation

¹ Unité de Chimie des Biomolécules, Institut Pasteur, Centre National de la Recherche Scientifique 2128, Paris, France.

PMID: 19734912
DOI: 10.1038/nchembio.207

Abstract

The HIV-1 envelope, gp120, which features the binding determinants for both CD4 and coreceptor recognition, is key for virus entry and represents an attractive pharmacological target. However, critical domains for entry (coreceptor and CD4 binding sites) are either cryptic or located in partially occluded cavities. Here we developed a chemical approach to synthesize a CD4-mimetic peptide linked to a heparan sulfate dodecasaccharide. This molecule binds to gp120, induces the exposure of the coreceptor binding domain and renders it available for interaction with the oligosaccharide. The linkage between the CD4 mimetic and the heparan sulfate derivative provides strong cooperative effects, resulting in low-nanomolar antiviral activity toward both CCR5- and CXCR4-tropic HIV-1 strains. This compound, which has the unique ability to simultaneously target two critical and highly conserved regions of gp120, establishes a new type of inhibitor and suggests a general concept for the inhibition of numerous other biological systems.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Binding Sites
CD4 Antigens / chemistry
CD4 Antigens / pharmacology*
Glycoconjugates / chemistry
Glycoconjugates / pharmacology*
HIV Envelope Protein gp120 / metabolism
HIV-1 / drug effects*
HIV-1 / physiology
Heparitin Sulfate / chemistry
Heparitin Sulfate / pharmacology*
Humans
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / metabolism
Leukocytes, Mononuclear / virology
Models, Molecular
Receptors, CCR5 / metabolism*
Receptors, CXCR4 / metabolism*
Virus Attachment / drug effects*
Virus Internalization / drug effects*

Substances

Anti-HIV Agents
CD4 Antigens
Glycoconjugates
HIV Envelope Protein gp120
Receptors, CCR5
Receptors, CXCR4
Heparitin Sulfate

Associated data

PubChem-Substance/85098842
PubChem-Substance/85098843
PubChem-Substance/85098844
PubChem-Substance/85098845
PubChem-Substance/85098846
PubChem-Substance/85098847
PubChem-Substance/85098848
PubChem-Substance/85098849
PubChem-Substance/85098850
PubChem-Substance/85098851
PubChem-Substance/85098852