AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor

Abstract

The bicyclam AMD3100 (formula weight 830) blocks HIV-1 entry and membrane fusion via the CXCR4 co-receptor, but not via CCR5. AMD3100 prevents monoclonal antibody 12G5 from binding to CXCR4, but has no effect on binding of monoclonal antibody 2D7 to CCR5. It also inhibits binding of the CXC-chemokine, SDF-1α, to CXCR4 and subsequent signal transduction, but does not itself cause signaling and has no effect on RANTES signaling via CCR5. Thus, AMD3100 prevents CXCR4 functioning as both a HIV-1 co-receptor and a CXC-chemokine receptor. Development of small molecule inhibitors of HIV-1 entry is feasible.

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    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  Google Scholar 

  2. 2

    Bleul, C.C., et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996).

    CAS  Article  Google Scholar 

  3. 3

    Oberlin, E., et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996).

    CAS  Article  Google Scholar 

  4. 4

    Premack, B.A. & Schall, T.J. Chemokine receptors: Gateways to inflammation and infection. Nature Med. 2, 1174–1178 (1996).

    CAS  Article  Google Scholar 

  5. 5

    Richman, D.D. & Bozzette, S.A. The impact of the syncytium inducing phenotype of human immunodeficiency virus on disease progression. J. Infect. Dis. 169, 968–974 (1994).

    CAS  Article  Google Scholar 

  6. 6

    Saag, M.S., Hammer, S.M. & Lange, J.M.A. Pathogenicity and diversity of HIV and implications for clinical management: A review. J. Acquir. Immune Defic. Syndr. 7 (Suppl.2), S2–S11 (1994).

    PubMed  Google Scholar 

  7. 7

    Connor, R.I. & Ho, D.D. Human immunodeficiency virus type 1 variants with increased replication capacity develop during the asymptomatic stage before disease progression. J. Virol. 68, 4400–4408 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Zhu, T., et al. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261, 1179–1181 (1993).

    CAS  Article  Google Scholar 

  9. 9

    Dragic, T. et al. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature 381, 667–673 (1996).

    CAS  Article  Google Scholar 

  10. 10

    Deng, H.K., et al. Identification of a major co-receptor for primary isolates of HIV-1. Nature 381, 661–666 (1996).

    CAS  Article  Google Scholar 

  11. 11

    Choe, H. et al. The β-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 86, 1135–1148 (1996).

    Article  Google Scholar 

  12. 12

    Doranz, B.J., et al. A dual-tropic, primary HIV-1 isolate that uses fusin and the β-chemokine receptors CKR-5, CKR 3, and CKR-2b as fusion cofactors. Cell 86, 1149–1159 (1996).

    Article  Google Scholar 

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

    Simmons, G., et al. Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry. J. Virol. 70, 8355–8360 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Connor, R.I., Sheridan, K.E., Ceradini, D., Choe, S. & Landau, N.R. Change in coreceptor use correlates with disease progression in HIV-1 infected individuals. J. Exp. Med. 185, 621–628 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Arenzana-Seisedos, F., et al. HIV blocked by chemokine antagonist. Nature 383, 400 (1996).

    Article  Google Scholar 

  17. 17

    Simmons, G., et al. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276, 276–279 (1997).

    CAS  Article  Google Scholar 

  18. 18

    De Clercq, E. et al. Potent and selective inhibition of human immunodeficiency virus (HIV)-I and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event. Proc. Natl. Acad. Sci. USA 89, 5286–5290 (1992).

    CAS  Article  Google Scholar 

  19. 19

    De Clercq, E. et al. Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100. Antimicrob. Agents Chemother. 38, 668–674 (1994).

    CAS  Article  Google Scholar 

  20. 20

    De Vreese, K. et al. The molecular target of bicyclams, potent inhibitors of human immunodeficiency virus replication. J. Virol. 70, 689–696 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    De Vreese, K. et al. The bicyclams, a new class of potent human immunodeficiency virus inhibitors, block viral entry after binding. Antiviral Res. 29, 209–219 (1996).

    CAS  Article  Google Scholar 

  22. 22

    Chen, B.K., Saksela, K., Andino, R. & Baltimore, D. Distinct modes of human immunodeficiency virus type 1 proviral latency revealed by superinfection of nonproductively infected cell lines with recombinant luciferase-encoding viruses. J. Virol. 68, 654–660 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Hill, C.M. et al. Envelope glycoproteins from HIV-1, HIV-2, and SIV can use human CCR5 as a cofactor for viral entry and make direct CD4-dependent interactions with this chemokine receptor. J. Virol. 71, 6296–6304 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Schols, D., Esté, J.A., Henson, G. & De Clercq, E., Bicyclams, a class of potent anti-HIV agents, are targeted at the HIV coreceptor fusin/CXCR4. Antiviral Res. 35, 147–156 (1997).

    CAS  Article  Google Scholar 

  25. 25

    Litwin, V. et al. Human immunodeficiency virus type 1 membrane fusion mediated by a laboratory-adapted strain and a primary isolate analyzed by resonance energy transfer. J. Virol. 70, 6437–6441 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Pantaleo, G. et al. Dissociation between syncytia formation and HIV spreading. Suppression of syncytia formation does not necessarily reflect inhibition of HIV infection. Eur. J. Immunol. 21, 1771–1774 (1993).

    Article  Google Scholar 

  27. 27

    Layne, S.P., Merges, M.J., Spouge, J.L., Dembo, M. & Nara, P.L. Blocking of human immunodeficiency virus infection depends on cell density and viral stock age. J. Virol. 65, 3293–3300 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Sylwester, A., Murphy, S., Shutt, D. & Soll, D.R. HIV-induced T cell syncytia are self-perpetuating and the primary cause of T cell death in culture. J. Immunol. 158, 3996–4007 (1997).

    CAS  PubMed  Google Scholar 

  29. 29

    Trkola, A. et al. CD4-dependent, antibody sensitive interactions between HIV-1 and its co-receptor CCR5. Nature 384, 184–186 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Wu, L. et al. CD4 induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384, 179–183 (1996).

    CAS  Article  Google Scholar 

  31. 31

    Moore, J.P. & Sodroski, J. Antibody cross-competition analysis of the human immunodeficiency virus type 1 exterior envelope glycoprotein. J. Virol. 70, 1863–1872 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Endres, M.J. etal. CD4 independent infection by HIV-2 is mediated byfusin/CXCR4. Cell 87, 745–756 (1996).

    CAS  Article  Google Scholar 

  33. 33

    Wu, L. et al. Interaction of chemokine receptor CCR5 with its ligands: Multiple domains for HIV-1 gp120 and a single domain for chemokine binding. J. Exp. Med. (in the press).

  34. 34

    McKnight, A. et al. Inhibition of human immunodeficiency virus fusion by a monoclonal antibody to a coreceptor (CXCR4) is both cell type and virus strain dependent. J. Virol. 71, 1692–1696 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Strizki, J.M. et al. A monoclonal antibody (12G5) directed against CXCR-4 inhibits infection with the dual-tropic human immunodeficiency virus type 1 isolate HIV-1 89.6 but not the T-tropic isolate HIV-1 HXB. J. Virol. 71, 5678–5691 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Lapham, C.K. et al. Evidence for cell-surface association between fusin and the CD4-gp120 complex in human cell lines. Science 274, 602–605 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Hesselgesser, J. et al. CD4-independent association between HIV-1 gp120 and CXCR4: Functional chemokine receptors are expressed in human neurons. Current Biol. 7, 112–121 (1997).

    CAS  Article  Google Scholar 

  38. 38

    Picard, L. et al. Role of the amino-terminal extracellular domain of CXCR-4 in human immunodeficiency virus type 1 entry. Virology 231, 105–111 (1997).

    CAS  Article  Google Scholar 

  39. 39

    Potemya, S. et al. CD4-independent infection by human immunodeficiency virus type 2 strain ROD/B: The role of the N-terminal domain of CXCR-4 in fusion and entry. J. Virol. 71, 4419–4424 (1997).

    Google Scholar 

  40. 40

    Brelot, A. et al. Role of the first and third extracellular domains of CXCR-4 in human immunodeficiency virus co-receptor activity. J. Virol. 71, 4744–4751 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Monteclaro, F.S. & Charo, I.F. The amino-terminal extracellular domain of the MCP-1 receptor, but not the RANTES/MIP-1 α receptor, confers chemokine selectivity. Evidence for a two-step mechanism for MCP-1 receptor activation. J. Biol. Chem. 271, 19084–19092 (1996).

    CAS  Article  Google Scholar 

  42. 42

    Wells, T.N.C. et al. Selectivity and antagonism of chemokine receptors. J. Leukocyte Biol. 59, 53–60 (1996).

    CAS  Article  Google Scholar 

  43. 43

    Datema, R. et al. Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM3100), an inhibitor of infectious cell entry. Antimicrob. Agents Chemother. 40, 750–754 (1996).

    CAS  Article  Google Scholar 

  44. 44

    Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–378 (1996).

    CAS  Article  Google Scholar 

  45. 45

    Samson, M. et al. Resistance to HIV-1 infection of Caucasian individuals bearing mutant alleles of the CKR5 chemokine receptor gene. Nature 382, 722–725 (1996).

    CAS  Article  Google Scholar 

  46. 46

    Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996).

    CAS  Article  Google Scholar 

  47. 47

    Trkola, A. et al. Genetic subtype-independent inhibition of human immunodeficiency virus type 1 replication by CC and CXC chemokines. J. Virol. (in the press).

  48. 48

    Koito, A., Stamatatos, L. & Cheng-Mayer, C. Small amino acid changes within the V2 domain can affect the function of a T-cell line tropic human immunodeficiency virus type 1 envelope gp120. Virology 206, 878–884 (1995).

    CAS  Article  Google Scholar 

  49. 49

    Shibata, R. et al. Isolation and characterization of a syncytium inducing macrophage/T-cell line tropic human immunodeficiency virus type 1 isolate that readily infects chimpanzee cells in vitro and in vivo. J. Virol. 69, 4453–4462 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Donzella, G., Schols, D., Lin, S. et al. AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 4, 72–77 (1998). https://doi.org/10.1038/nm0198-072

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