A Synthetic Heparan Sulfate-Mimetic Peptide Conjugated to a Mini CD4 Displays Very High Anti- HIV-1 Activity Independently of Coreceptor Usage. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Chem Biol Année : 2012

A Synthetic Heparan Sulfate-Mimetic Peptide Conjugated to a Mini CD4 Displays Very High Anti- HIV-1 Activity Independently of Coreceptor Usage.

Résumé

The HIV-1 envelope gp120, which features both the virus receptor (CD4) and coreceptor (CCR5/CXCR4) binding sites, offers multiple sites for therapeutic intervention. However, the latter becomes exposed, thus vulnerable to inhibition, only transiently when the virus has already bound cellular CD4. To pierce this defense mechanism, we engineered a series of heparan sulfate mimicking tridecapeptides and showed that one of them target the gp120 coreceptor binding site with μM affinity. Covalently linked to a CD4-mimetic that binds to gp120 and renders the coreceptor binding domain available to be targeted, the conjugated tridecapeptide now displays nanomolar affinity for its target. Using solubilized coreceptors captured on top of sensorchip we show that it inhibits gp120 binding to both CCR5 and CXCR4 and in peripheral blood mononuclear cells broadly inhibits HIV-1 replication with an IC(50) of 1 nM.
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Dates et versions

hal-00664771 , version 1 (31-01-2012)

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Bridgette Janine Connell, Françoise Baleux, Yves-Marie Coic, Pascal Clayette, David Bonnaffé, et al.. A Synthetic Heparan Sulfate-Mimetic Peptide Conjugated to a Mini CD4 Displays Very High Anti- HIV-1 Activity Independently of Coreceptor Usage.. Chem Biol, 2012, 19 (1), pp.131-9. ⟨10.1016/j.chembiol.2011.12.009⟩. ⟨hal-00664771⟩
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