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Sci Rep. 2016 Oct 10;6:34829. doi: 10.1038/srep34829.

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

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Institute of Tropical Medicine, Virology Unit, Antwerp, Belgium.
Institut Pasteur, Unité de Chimie des Biomolécules, UMR CNRS 3523, 75015 Paris, France.
CEA, DRF/iMETI, IMVA-UMR1184, IDMIT infrastructure, Fontenay-aux-Roses, France.
Université Paris-Sud, UMR1184, Fontenay-aux-Roses, France.
Inserm, UMR1184, Center for Immunology of Viral Infections and Autoimmune Diseases (IMVA), Fontenay-aux-Roses, France.
Institut Pasteur, UMR CNRS 3569, Paris France.
Institut Galien Paris Sud, UMR CNRS 8612, Faculté de Pharmacie, Univ. Paris-Sud, Université Paris-Saclay, 92296 Chatenay-Malabry, France.
Institut de Chimie Moléculaire et des Matériaux d'Orsay, UMR 8182, LabEx LERMIT, Univ Paris Sud, CNRS, Université Paris-Saclay, Orsay, France.
University of Antwerp, Department of Biomedical Sciences, Belgium.
Institut de Biologie Structurale, UMR5075 CNRS, CEA, Université Grenoble-Alpes, 38027 Grenoble, France.


The 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.

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