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. 1997 Dec;41(12):2616–2620. doi: 10.1128/aac.41.12.2616

Sensitivity of human immunodeficiency virus to bicyclam derivatives is influenced by the three-dimensional structure of gp120.

K De Vreese 1, I Van Nerum 1, K Vermeire 1, J Anné 1, E De Clercq 1
PMCID: PMC164179  PMID: 9420029

Abstract

The bicyclams are a new class of anti-human immunodeficiency virus (anti-HIV) compounds targeted at viral entry. From marker rescue experiments, it appears that the envelope gp120 glycoprotein plays an important role in the anti-HIV activity of the bicyclams. Bicyclam-resistant strains contain a number of amino acid changes scattered over the V2 to V5 region of gp120. Experiments aimed at estimating the relative importance of particular amino acid changes with regard to the overall resistance pattern are described. The sequences of some partially bicyclam-resistant virus strains, obtained during the resistance development process, were analyzed, and the corresponding 50% effective concentrations were determined. Selected mutations observed in bicyclam-resistant strains were introduced in the wild-type background by site-directed mutagenesis. In addition, some amino acids were back-mutated to their wild-type counterparts in an otherwise JM3100-resistant strain. The sensitivities of these mutant viruses to bicyclams were determined. Construction of chimeric viruses, carrying the V3 loop of JM3100-resistant virus in a wild-type HIV type 1 HXB2 background, enabled us to investigate the importance of the mutations in the V3 loop of JM3100-resistant virus. From the results described in the report, it can be concluded that single amino acid substitutions do not influence the observed resistance to JM3100. Also, the mutations in the V3 loop are not sufficient to engender even a partially resistant phenotype. We postulate that the overall conformation of gp120 determines the degree of sensitivity or resistance of HIV strains to bicyclams.

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Selected References

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  1. Bridger G. J., Skerlj R. T., Thornton D., Padmanabhan S., Martellucci S. A., Henson G. W., Abrams M. J., Yamamoto N., De Vreese K., Pauwels R. Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit HIV replication. Effects of macrocyclic ring size and substituents on the aromatic linker. J Med Chem. 1995 Jan 20;38(2):366–378. doi: 10.1021/jm00002a019. [DOI] [PubMed] [Google Scholar]
  2. Catasti P., Fontenot J. D., Bradbury E. M., Gupta G. Local and global structural properties of the HIV-MN V3 loop. J Biol Chem. 1995 Feb 3;270(5):2224–2232. doi: 10.1074/jbc.270.5.2224. [DOI] [PubMed] [Google Scholar]
  3. De Clercq E., Yamamoto N., Pauwels R., Baba M., Schols D., Nakashima H., Balzarini J., Debyser Z., Murrer B. A., Schwartz D. Potent and selective inhibition of human immunodeficiency virus (HIV)-1 and HIV-2 replication by a class of bicyclams interacting with a viral uncoating event. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5286–5290. doi: 10.1073/pnas.89.12.5286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. De Clercq E., Yamamoto N., Pauwels R., Balzarini J., Witvrouw M., De Vreese K., Debyser Z., Rosenwirth B., Peichl P., Datema R. Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100. Antimicrob Agents Chemother. 1994 Apr;38(4):668–674. doi: 10.1128/aac.38.4.668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. De Vreese K., Reymen D., Griffin P., Steinkasserer A., Werner G., Bridger G. J., Esté J., James W., Henson G. W., Desmyter J. The bicyclams, a new class of potent human immunodeficiency virus inhibitors, block viral entry after binding. Antiviral Res. 1996 Mar;29(2-3):209–219. doi: 10.1016/0166-3542(95)00837-3. [DOI] [PubMed] [Google Scholar]
  6. Esté J. A., De Vreese K., Witvrouw M., Schmit J. C., Vandamme A. M., Anné J., Desmyter J., Henson G. W., Bridger G., De Clercq E. Antiviral activity of the bicyclam derivative JM3100 against drug-resistant strains of human immunodeficiency virus type 1. Antiviral Res. 1996 Mar;29(2-3):297–307. doi: 10.1016/0166-3542(95)00936-1. [DOI] [PubMed] [Google Scholar]
  7. Freed E. O., Martin M. A. Evidence for a functional interaction between the V1/V2 and C4 domains of human immunodeficiency virus type 1 envelope glycoprotein gp120. J Virol. 1994 Apr;68(4):2503–2512. doi: 10.1128/jvi.68.4.2503-2512.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Harada S., Koyanagi Y., Yamamoto N. Infection of HTLV-III/LAV in HTLV-I-carrying cells MT-2 and MT-4 and application in a plaque assay. Science. 1985 Aug 9;229(4713):563–566. doi: 10.1126/science.2992081. [DOI] [PubMed] [Google Scholar]
  9. Moore J. P., Willey R. L., Lewis G. K., Robinson J., Sodroski J. Immunological evidence for interactions between the first, second, and fifth conserved domains of the gp120 surface glycoprotein of human immunodeficiency virus type 1. J Virol. 1994 Nov;68(11):6836–6847. doi: 10.1128/jvi.68.11.6836-6847.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Okada T., Gurney M. E. Single basic amino acid substitutions at position 302 or 320 in the V3 domain of HIV type 1 are not sufficient to alter the antiviral activity of dextran sulfate and heparin. AIDS Res Hum Retroviruses. 1995 May;11(5):571–575. doi: 10.1089/aid.1995.11.571. [DOI] [PubMed] [Google Scholar]
  11. Pauwels R., Balzarini J., Baba M., Snoeck R., Schols D., Herdewijn P., Desmyter J., De Clercq E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods. 1988 Aug;20(4):309–321. doi: 10.1016/0166-0934(88)90134-6. [DOI] [PubMed] [Google Scholar]
  12. Ryser H. J., Levy E. M., Mandel R., DiSciullo G. J. Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4559–4563. doi: 10.1073/pnas.91.10.4559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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/CXCR-4. Antiviral Res. 1997 Aug;35(3):147–156. doi: 10.1016/s0166-3542(97)00025-9. [DOI] [PubMed] [Google Scholar]
  14. Willey R. L., Ross E. K., Buckler-White A. J., Theodore T. S., Martin M. A. Functional interaction of constant and variable domains of human immunodeficiency virus type 1 gp120. J Virol. 1989 Sep;63(9):3595–3600. doi: 10.1128/jvi.63.9.3595-3600.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Wyatt R., Thali M., Tilley S., Pinter A., Posner M., Ho D., Robinson J., Sodroski J. Relationship of the human immunodeficiency virus type 1 gp120 third variable loop to a component of the CD4 binding site in the fourth conserved region. J Virol. 1992 Dec;66(12):6997–7004. doi: 10.1128/jvi.66.12.6997-7004.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. de Jong J. J., Goudsmit J., Keulen W., Klaver B., Krone W., Tersmette M., de Ronde A. Human immunodeficiency virus type 1 clones chimeric for the envelope V3 domain differ in syncytium formation and replication capacity. J Virol. 1992 Feb;66(2):757–765. doi: 10.1128/jvi.66.2.757-765.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. de Vreese K., Kofler-Mongold V., Leutgeb C., Weber V., Vermeire K., Schacht S., Anné J., de Clercq E., Datema R., Werner G. The molecular target of bicyclams, potent inhibitors of human immunodeficiency virus replication. J Virol. 1996 Feb;70(2):689–696. doi: 10.1128/jvi.70.2.689-696.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

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