Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

References

  1. 1

    Barre-Sinoussi, F. et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868–871 (1983).

    CAS  Article  PubMed  Google Scholar 

  2. 2

    Shafer, R.W. & Schapiro, J.M. HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. AIDS Rev. 10, 67–84 (2008).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Flexner, C. HIV drug development: the next 25 years. Nat. Rev. Drug Discov. 6, 959–966 (2007).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Klatzmann, D. et al. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Nature 312, 767–768 (1984).

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Alkhatib, G. et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science 272, 1955–1958 (1996).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Feng, Y., Broder, C.C., Kennedy, P.E. & Berger, E.A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Berger, E.A., Murphy, P.M. & Farber, J.M. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 17, 657–700 (1999).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Chen, B. et al. Structure of an unliganded simian immunodeficiency virus gp120 core. Nature 433, 834–841 (2005).

    CAS  Article  PubMed  Google Scholar 

  9. 9

    Kwong, P.D. et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393, 648–659 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Hartley, O., Klasse, P.J., Sattentau, Q.J. & Moore, J.P. V3: HIV's switch-hitter. AIDS Res. Hum. Retroviruses 21, 171–189 (2005).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Rizzuto, C.D. et al. A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding. Science 280, 1949–1953 (1998).

    CAS  Article  PubMed  Google Scholar 

  12. 12

    Bishop, J.R., Schuksz, M. & Esko, J.D. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature 446, 1030–1037 (2007).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Endress, T. et al. HIV-1-cellular interactions analyzed by single virus tracing. Eur. Biophys. J. 37, 1291–1301 (2008).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    de Witte, L. et al. Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1. Proc. Natl. Acad. Sci. USA 104, 19464–19469 (2007).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Rider, C.C. et al. Anti-HIV-1 activity of chemically modified heparins: correlation between binding to the V3 loop of gp120 and inhibition of cellular HIV-1 infection in vitro. Biochemistry 33, 6974–6980 (1994).

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Roderiquez, G. et al. Mediation of human immunodeficiency virus type 1 binding by interaction of cell surface heparan sulfate proteoglycans with the V3 region of envelope gp120-gp41. J. Virol. 69, 2233–2239 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Moulard, M. et al. Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp120. J. Virol. 74, 1948–1960 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Crublet, E., Andrieu, J.P., Vives, R.R. & Lortat-Jacob, H. The HIV-1 envelope glycoprotein gp120 features four heparan sulfate binding domains, including the co-receptor binding site. J. Biol. Chem. 283, 15193–15200 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19

    Vives, R.R., Imberty, A., Sattentau, Q.J. & Lortat-Jacob, H. Heparan sulfate targets the HIV-1 envelope glycoprotein gp120 coreceptor binding site. J. Biol. Chem. 280, 21353–21357 (2005).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Pierson, T.C. & Doms, R.W. HIV-1 entry and its inhibition. Curr. Top. Microbiol. Immunol. 281, 1–27 (2003).

    CAS  PubMed  Google Scholar 

  21. 21

    Huang, C.C. et al. Scorpion-toxin mimics of CD4 in complex with human immunodeficiency virus gp120 crystal structures, molecular mimicry, and neutralization breadth. Structure 13, 755–768 (2005).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Adibekian, A. et al. De novo synthesis of uronic acid building blocks for assembly of heparin oligosaccharides. Chemistry (Easton) 13, 4510–4522 (2007).

    CAS  Google Scholar 

  23. 23

    Lubineau, A., Lortat-Jacob, H., Gavard, O., Sarrazin, S. & Bonnaffe, D. Synthesis of tailor-made glycoconjugate mimetics of heparan sulfate that bind IFN-gamma in the nanomolar range. Chemistry (Easton) 10, 4265–4282 (2004).

    CAS  Google Scholar 

  24. 24

    Petitou, M. & van Boeckel, C.A. A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next? Angew. Chem. Int. Edn Engl. 43, 3118–3133 (2004).

    CAS  Article  Google Scholar 

  25. 25

    Xiang, S.H., Doka, N., Choudhary, R.K., Sodroski, J. & Robinson, J.E. Characterization of CD4-induced epitopes on the HIV type 1 gp120 envelope glycoprotein recognized by neutralizing human monoclonal antibodies. AIDS Res. Hum. Retroviruses 18, 1207–1217 (2002).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Choe, H. et al. Tyrosine sulfation of human antibodies contributes to recognition of the CCR5 binding region of HIV-1 gp120. Cell 114, 161–170 (2003).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Huang, C.C. et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4. Science 317, 1930–1934 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Roisin, A. et al. Inhibition of HIV-1 replication by cell-penetrating peptides binding Rev. J. Biol. Chem. 279, 9208–9214 (2004).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Labrijn, A.F. et al. Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1. J. Virol. 77, 10557–10565 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Chen, W., Zhu, Z., Feng, Y. & Dimitrov, D.S. Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers. Proc. Natl. Acad. Sci. USA 105, 17121–17126 (2008).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Saidi, H., Magri, G., Nasreddine, N., Requena, M. & Belec, L. R5- and X4-HIV-1 use differentially the endometrial epithelial cells HEC-1A to ensure their own spread: implication for mechanisms of sexual transmission. Virology 358, 55–68 (2007).

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Argyris, E.G. et al. Human immunodeficiency virus type 1 enters primary human brain microvascular endothelial cells by a mechanism involving cell surface proteoglycans independent of lipid rafts. J. Virol. 77, 12140–12151 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Moncunill, G., Armand-Ugon, M., Pauls, E., Clotet, B. & Este, J.A. HIV-1 escape to CCR5 coreceptor antagonism through selection of CXCR4-using variants in vitro. AIDS 22, 23–31 (2008).

    CAS  Article  PubMed  Google Scholar 

  34. 34

    Chan, W.C. & White, P.D. Fmoc Solid Phase Peptide Synthesis, a Practical Approach (Oxford University Press, Oxford, 2000).

    Google Scholar 

  35. 35

    Gartner, S. et al. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233, 215–219 (1986).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Kärber, G. Beitrag zur kollektiven behandlung pharmakologischer reihenversuche. Arch. Exp. Path. Pharmak. 162, 480–483 (1931).

    Article  Google Scholar 

  37. 37

    Thali, M. et al. Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120–CD4 binding. J. Virol. 67, 3978–3988 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Affiliations

Authors

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.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing