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CD4-mimetic sulfopeptide conjugates display sub-nanomolar anti-HIV-1 activity and protect macaques against a SHIV162P3 vaginal challenge.

By Kevin K Ariën, Françoise Baleux, Delphine Desjardins, Françoise Porrot, Yves-Marie Coïc, Johan Michiels, Kawthar Bouchemal, David Bonnaffé, Timothée Bruel, Olivier Schwartz, Roger Le Grand, Guido Vanham, Nathalie Dereuddre-Bosquet and Hugues Lortat-Jacob

Abstract

International audienceThe CD4 and the cryptic coreceptor binding sites of the HIV-1 envelope glycoprotein are key to viral attachment and entry. We developed new molecules comprising a CD4 mimetic peptide linked to anionic compounds (mCD4.1-HS12 and mCD4.1-PS1), that block the CD4-gp120 interaction and simultaneously induce the exposure of the cryptic coreceptor binding site, rendering it accessible to HS12- or PS1- mediated inhibition. Using a cynomolgus macaque model of vaginal challenge with SHIV162P3, we report that mCD4.1-PS1, formulated into a hydroxyethyl-cellulose gel provides 83% protection (5/6 animals). We next engineered the mCD4 moiety of the compound, giving rise to mCD4.2 and mCD4.3 that, when conjugated to PS1, inhibited cell-free and cell-associated HIV-1 with particularly low IC50, in the nM to pM range, including some viral strains that were resistant to the parent molecule mCD4.1. These chemically defined molecules, which target major sites of vulnerability of gp120, are stable for at least 48 hours in conditions replicating the vaginal milieu (37 °C, pH 4.5). They efficiently mimic several large gp120 ligands, including CD4, coreceptor or neutralizing antibodies, to which their efficacy compares very favorably, despite a molecular mass reduced to 5500 Da. Together, these results support the development of such molecules as potential microbicides

Topics: heparan sulfate mimetic, CCR5, CXCR4, sulfopeptide, HIV, gp120, CD4, CD4-mimetic, entry inhibitor, preclinical study, heparan sulfate mimetic, CCR5, CXCR4, sulfopeptide, HIV, gp120, CD4, CD4-mimetic, entry inhibitor, preclinical study, [ CHIM.THER ] Chemical Sciences/Medicinal Chemistry, [ SDV.MP.VIR ] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Publisher: Nature Publishing Group
Year: 2016
DOI identifier: 10.1038/srep34829
OAI identifier: oai:HAL:pasteur-01423094v1
Provided by: Hal-Diderot
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