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

Nature Chemical Biology volume 5, pages 743–748 (2009)Cite this article

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.

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Figure 1: HIV entry and principle of inhibition by 'CD4-HS'.
Figure 2: Inhibition of gp120 binding to CD4, HS and monoclonal antibody 17b by mCD4g, HS12 or mCD4-HS12.
Figure 3: The mCD4-HS12 binds to gp120 and unmasks and blocks the gp120 coreceptor binding site.

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Acknowledgements

We thank L. Klemm, C. Rogez-Kreuz, R. Yousfi and V. Huyot for technical assistance and R.R. Vivès for stimulating discussions. This work was supported by the Agence Nationale de la Recherche sur le Syndrome d'Immunodficience Acquise. Soluble CD4 and monoclonal antibodies 17b and E51 were obtained through the US National Institutes of Health AIDS Research and Reference Reagent Program from S. Iyer and J. Robinson. Infectious HIV-1 proviral clones pNL4-3 Luc were a gift from J. Alcami (Unidad de Inmunopatologa del Sida, Instituto de Salud Carlos III).

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Authors and Affiliations

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

    Françoise Baleux

  2. Laboratoire de Chimie Organique Multifonctionnelle, Equipe Glycochimie Moléculaire et Macromoléculaire, Institut de Chimie Moléculaire et des Matériaux d'Orsay, Unité Mixe de Recherche 8182, Centre National de la Recherche Scientifique, Université Paris-Sud, Orsay, France

    Latino Loureiro-Morais, Yael Hersant & David Bonnaffé

  3. Laboratoire de Neurovirologie, SPI-Bio, Commissariat à l'Energie Atomique, Fontenay aux Roses, France

    Pascal Clayette

  4. Institut Pasteur, laboratoire de Pathogénie Virale, Institut National de la Science et de la Recherche Médicale, Unité U819, Paris, France

    Fernando Arenzana-Seisdedos

  5. Institut de Biologie Structurale, Unité Mixe de Recherche 5075, Centre National de la Recherche Scientifique, Commissariat à l'Energie Atomique, Université Joseph Fourier, Grenoble, France

    Hugues Lortat-Jacob

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Contributions

H.L.-J. developed the hypotheses; F.B., D.B. and H.L.-J. designed the project and wrote the manuscript; F.B., D.B., L.L.-M. and Y.H. synthesized and characterized the molecules; H.L.-J. performed the binding studies; P.C. and F.A.-S. performed the antiviral analyses.

Corresponding author

Correspondence to Hugues Lortat-Jacob.

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Supplementary Figures 1–4, Supplementary Schemes 1–3, Supplementary Table 1 and Supplementary Methods (PDF 2736 kb)

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Baleux, F., Loureiro-Morais, L., Hersant, Y. et al. A synthetic CD4–heparan sulfate glycoconjugate inhibits CCR5 and CXCR4 HIV-1 attachment and entry. Nat Chem Biol 5, 743–748 (2009). https://doi.org/10.1038/nchembio.207

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