Iminosugar glycosylation inhibitors as anti-HIV agents

Summary

A novel class of compounds which are potent inhibitors of the posttranslational glycan trimming enzyme α-glucosidase I have been found to display anti-HIV activity. These compounds are iminosugar analogs ofd-glucose, with the oxygen in the ring replaced by a nitrogen, and were originally isolated from plants and microorganisms, although a considerable number of analogs have been synthesized during the past few years. One of these compounds,N-butyl-1-deoxynojirimycin (Bu-DNJ), is presently under evaluation in clinical trials for the control of HIV infections. Cumulative data, to date, suggest that compounds such asN-Bu-DNJ have a hierarchy of effects, with reduction in syncytia formation being the predominant feature, and are known to alter glycosylation of the HIV-1 envelope glycoproteins gp120 and gp41. Consequently, there are a number of different ways in which iminosugars may be exerting an antiviral effect. This paper discusses the basic properties of this class of compounds and the changes they effect in posttranslational processing of gp120 and gp41, as well as the synthesis and characterization of prodrug forms of Bu-DNJ (e.g.N-butyl-6-phospho-1-deoxynojirimycin), which do not inhibit intestinal disaccharidases and may be useful for eliminating the intestinal discomfort and diarrhea associated with administration of α-glucosidase inhibitors.

This is a preview of subscription content, access via your institution.

References

  1. 1

    Joubert, P.H., Venter, C.P., Joubert, H.F. and Hillebrand, I., Eur.J. Pharmacol., 28 (1985) 705.

    Google Scholar 

  2. 2

    Joubert, P.H., Bam, W.J. and Manyane, N., Eur. J. Clin. Pharmacol., 30 (1986) 253.

    Google Scholar 

  3. 3

    Schnack, Ch., Röggla, G., Luger, A. and Schernthaner, G., Eur. J. Clin. Pharmacol., 30 (1986) 417.

    Google Scholar 

  4. 4

    Hillebrand, I., Boehme, K., Graefe, K.H. and Wehling, K., Klin. Wochenschr., 6 (1986) 393.

    Google Scholar 

  5. 5

    Dimitriadis, G., Raptis, S., Raptis, A., Hatziagelaki, E., Mitrakou, A., Halvatsiotis, P., Ladas, S. and Hillebrand, I., Klin. Wochensch., 64 (1986) 405.

    Google Scholar 

  6. 6

    Schmidt, D.D., Frommer, W., Junge, B., Muller, L., Wingender, W. and Truscheit, E., Naturwissenschaften, 64 (1977) 535.

    Google Scholar 

  7. 7

    Gruters, R.A., Neefjes, J.J., Tersmette, M., De Goede, R.E.Y., Tulp, A., Huisman, H.G., Miedema, F. and Ploegh, H.L., Nature, 330 (1987) 74.

    Google Scholar 

  8. 8

    Walker, B.D., Kowalski, M., Goh, W.C., Kozarsky, K., Krieger, M., Rosen, C., Rohrschneider, L., Haseltine, W.A. and Sodroski, J., Proc. Natl. Acad. Sci. USA, 84 (1987) 8120.

    Google Scholar 

  9. 9

    Tyms, A.S., Berrie, E.M., Ryder, T.A., Nash, R.J., Hegarty, M.P., Taylor, T.L., Mobberly, M.A., Davis, J.M., Bell, E.A., Jeffries, D.J., Taylor-Robinson, D. and Fellows, L.E., Lancet (1987) 1025.

  10. 10

    Fleet, G.W.J., Karpas, A., Dwek, R.A., Fellows, L.E., Tyms, A.C., Petursson, S., Namgoong, S.K., Ramsden, N.J., Smith, P.W., Son, J.C., Wilson, F., Witty, D.R., Jacob, G.S. and Rademacher, T.W., FEBS Lett., 237 (1988) 128.

    Google Scholar 

  11. 11

    Karpas, A., Fleet, G.W.J., Dwek, R.A., Petursson, S., Namgoong, S.K., Ramsden, N.G., Jacob, G.S. and Rademacher, T.W., Proc. Natl. Acad. Sci. USA, 85 (1988) 9229.

    Google Scholar 

  12. 12

    Sunkara, P.S., Taylor, D.L., Kang, M.S., Bowlin, T.L., Liu, P.S., Tyms, A.S. and Sjoerdsma, A., Lancet (1989) 1206.

  13. 13

    Leonard, C.K., Spellman, M.W., Riddle, L., Harris, R.J., Thomas, J.N. and Gregory, T.J., J. Biol. Chem., 265 (1990) 10373.

    Google Scholar 

  14. 14

    Geyer, H., Hoschbach, C., Hunsmann, G. and Schneider, J., J. Biol. Chem., 263 (1988) 11760.

    Google Scholar 

  15. 15

    Mizuochi, T., Spellman, M.W., Larkin, M., Solomon, J., Basa, L.J. and Feizi, T., Biochem. J., 254 (1988) 599.

    Google Scholar 

  16. 16

    Mizuochi, T., Matthews, T.J., Kato, M., Hamako, J., Titani, K., Solomon, J. and Feizi, T., J. Biol. Chem., 265 (1990) 8519.

    Google Scholar 

  17. 17

    Butters, T.D., Jones, I., Clarke, V.A. and Jacob, G.S., Glycoconjugate J., 8 (1991) 240.

    Google Scholar 

  18. 18

    Jacob, G.S., Scudder, P., Butters, T.D., Jones, I. and Tiemeier, D.C., In Chu, C.K. and Cutler, H.G. (Eds.) Natural Products as Antiviral Agents, Plenum Press, New York, 1992, pp. 137–152.

    Google Scholar 

  19. 19

    Morikawa, Y., Overton, H.A., Moore, J.P., Wilkinson, A.J., Brady, R.L., Lewis, S.J. and Jones, I.M., AIDS Res. Hum. Retrov., 6 (1990) 765.

    Google Scholar 

  20. 20

    Fenouillet, E., Gluckman, J.C. and Bahraoui, E., J. Virol., 64 (1990) 2841.

    Google Scholar 

  21. 21

    Elbein, A.D., In Ginsberg, V. (Ed.) Methods in Enzymology, Vol. 138, Academic Press, New York, 1987, pp. 661–709.

    Google Scholar 

  22. 22

    Elbein, A.D., FASEB J., 5 (1991) 3055.

    Google Scholar 

  23. 23

    Winchester, B. and Fleet, G.W.J., Glycobiology, 2 (1992) 199.

    Google Scholar 

  24. 24

    Elbein, A.D., Mitchell, M., Sandford, B.A., Fellows, L.E. and Evans, S.V., J. Biol. Chem., 259 (1984) 12409.

    Google Scholar 

  25. 25

    Elbein, A.D., Legler, G., Tlusty, A., McDowell, W. and Schwarz, R., Arch. Biochem. Biophys., 235 (1984) 579.

    Google Scholar 

  26. 26

    Bischoff, J., Liscum, L. and Kornfeld, R., J. Biol. Chem., 261 (1986) 4766.

    Google Scholar 

  27. 27

    Platt, M., Karlsson, G.B. and Jacob, G.S., Eur. J. Biochem., 208 (1992) 187.

    Google Scholar 

  28. 28

    Lubas, W.A. and Spiro, R.G., J. Biol. Chem., 262 (1987) 3775.

    Google Scholar 

  29. 29

    Lubas, W.A. and Spiro, R.G., J. Biol. Chem., 263 (1988) 3990.

    Google Scholar 

  30. 30

    Rabouille, C. and Spiro, R.G., J. Biol. Chem., 267 (1992) 11573.

    Google Scholar 

  31. 31

    Ratner, L., Van der Heyden, N.V. and Dedera, D., Virology, 181 (1991) 180.

    Google Scholar 

  32. 32

    Dedera, D., Van der Heyden, N. and Ratner, L., AIDS Res. Hum. Retrov., 6 (1990) 785.

    Google Scholar 

  33. 33

    Karlsson, G.B., Butters, T.D., Dwek, R.A. and Platt, F.M., J. Biol. Chem., 268 (1993) 570.

    Google Scholar 

  34. 34

    Sunkara, P.S., Bowlin, T.L., Liu, P.S. and Sjoerdsma, A., Biochem. Biophys. Res. Commun., 148 (1987) 206.

    Google Scholar 

  35. 35

    Ruprecht, R.M., Mullaney, S., Andersen, J. and Bronson, R., J. Acquir. Immun. Def. Syndr., 2 (1989) 149.

    Google Scholar 

  36. 36

    Taylor, D.L., Fellows, L.E., Farrar, G.H., Nash, R.J., Taylor-Robinson, D., Mobberley, M.A., Ryder, T.A., Jeffries, D.J. and Tyms, A.S., Antiviral Res., 10 (1988) 11.

    Google Scholar 

  37. 37

    Schols, D., Pauwels, R., Witvrouw, M., Desmyter, J. and De Clercq, E., Antivir. Chem. Chemother., 3 (1992) 23.

    Google Scholar 

  38. 38

    Johnson, V.A., Walker, B.D., Barlow, M.A., Paradis, T.J., Chou, T.-C. and Hirsch, M.S., Antimicrob. Agents Chemother., 33 (1989) 53.

    Google Scholar 

  39. 39

    Hollingshead, M.G., Westbrook, L., Toyer, B.J. and Allen, L.B., Antivir. Chem. Chemother., 2 (1991) 119.

    Google Scholar 

  40. 40

    Sunkara, P.S., Taylor, D.L., Kang, M.S., Bowlin, T.L., Liu, P.S., Tyms, A.S. and Sjoerdsma, A., Lancet (1989) 1206.

  41. 41

    Sunkara, P.S., Kang, M.S., Bowlin, T.L., Liu, P.S., Tyms, A.S. and Sjoerdsma, A., Ann. New York Acad. Sci., 616 (1990) 90.

    Google Scholar 

  42. 42

    Ruprecht, R.M., Bernard, L.D., Bronson, R., Gama Sosa, M.A. and Mullaney, S., J. Acquir. Immun. Def. Syndr., 4 (1991) 48.

    Google Scholar 

  43. 43

    Inouye, S., Tsurouka, T., Ito, T. and Niida, T., Tetrhedron, 24 (1968) 2125.

    Google Scholar 

  44. 44

    Yagi, M., Kuono, T., Aoyagi, Y. and Murai, H., Nippon Nogei Kagaku Kaishi, 50 (1976) 571.

    Google Scholar 

  45. 45

    Murao, S. and Miyata, S., Agric. Biol. Chem., 44 (1980) 219.

    Google Scholar 

  46. 46

    Schweden, J., Borgmann, C., Legler, G. and Bause, E., Arch. Biochem. Biophys., 248 (1986) 335.

    Google Scholar 

  47. 47

    Shimizu, H., Tsuchie, H., Yoshida, K., Morikawa, S., Tsuruoka, T., Yamamoto, H., Ushijima, H. and Kitamura, T., AIDS, 4 (1990) 975.

    Google Scholar 

  48. 48

    Yoshikuni, Y. and Nakane, M. (Nippon Shinyaku Co., Ltd.), Antiviral Drug, Japanese Patent 91512435.

  49. 49

    Mathews, T.J., Weinhold, K.J., Lyerly, H.K., Langlois, A.J., Wigzell, H. and Bolognesi, D.P., Proc. Natl. Acad. Sci. USA, 84 (1987) 5424.

    Google Scholar 

  50. 50

    Bahraoui, E., Benjouad, A., Guetard, D., Kolbe, H., Gluckman, J.-C. and Montagnier, L., AIDS Res. Hum. Retrov., 8 (1992) 565.

    Google Scholar 

  51. 51

    Ratner, L., AIDS Res. Hum. Retrov., 8 (1992) 165.

    Google Scholar 

  52. 52

    McCune, J.M., Rabin, L.B., Feinberg, M.B., Lieberman, M., Kosek, J.C., Reyes, G.R. and Weissman, I.L., Cell, 53 (1988) 55.

    Google Scholar 

  53. 53

    Freed, E.O., Myers, D.J. and Risser, R., J. Virol., 63 (1989) 4650.

    Google Scholar 

  54. 54

    Bosch, V. and Pawlita, M., J. Virol., 64 (1990) 2337.

    Google Scholar 

  55. 55

    Guo, H.-G., Veronese, F.D., Tschachler, E., Pal, R., Kalyanaraman, V.S., Gallo, R.C. and Reitz, M.S., Virology, 174 (1990) 217.

    Google Scholar 

  56. 56

    Hallenberger, S., Bosch, V., Angliker, H., Shaw, E., Klenk, H.-D. and Garten, W., Nature, 360 (1992) 358.

    Google Scholar 

  57. 57

    Steiner, D.F., Smeekens, S.P., Ohagi, S. and Chan, S.J., J. Biol. Chem., 267 (1992) 23435.

    Google Scholar 

  58. 58

    Jones, I.M. and Jacob, G.S., Nature, 352 (1991) 198.

    Google Scholar 

  59. 59

    Hattori, T., Koito, A., Takatsuki, K., Kido, H. and Katunuma, N., FEBS Lett., 248 (1989) 48.

    Google Scholar 

  60. 60

    Stephens, P.E., Clements, G., Yarranton, G.T. and Moore, J.P., Nature, 343 (1990) 219.

    Google Scholar 

  61. 61

    Clements, G.J., Price-Jones, M.J., Stephens, P.E., Sutton, C., Schulz, T.F., Clapham, P.R., McKeating, J.A., McClure, M.O., Thomson, S., Marsh, M., Kay, J., Weiss, R.A. and Moore, J.P., AIDS Res. Hum. Retrov., 7 (1991) 3.

    Google Scholar 

  62. 62

    Ivanoff, L.A., Looney, D.J., McDanal, C., Morris, J.F., Wong-Staal, F., Langlois, A.J., Petteway, S.R. and Matthews, T.J., AIDS Res. Hum. Retrov., 7 (1991) 595.

    Google Scholar 

  63. 63

    Scofield, A.M., Fellows, L.E., Nash, R.J. and Fleet, G.W.J., Life Sci., 39 (1988) 645.

    Google Scholar 

  64. 64

    Yoshikuni, Y., Ezure, Y., Aoyagi, Y. and Enomoto, H., J. Pharmacobio-Dyn., 11 (1988) 356.

    Google Scholar 

  65. 65

    Yoshikuni, Y., Agric. Biol. Chem., 52 (1988) 121.

    Google Scholar 

  66. 66

    Hanozet, G., Pircher, H.-P., Vanni, P., Oesch, B. and Semenza, G., J. Biol. Chem., 256 (1981) 3703.

    Google Scholar 

  67. 67

    Trugnan, G., Rousset, M. and Zweibaum, A., FEBS Lett., 195 (1986) 28.

    Google Scholar 

  68. 68

    Fernley, H.N., In Boyer, P.D. (Ed.) The Enzymes, Academic Press, New York, 1971, pp. 417–447.

    Google Scholar 

  69. 69

    Hettkamp, H., Legler, G. and Bause, E., Eur. J. Biochem., 142 (1984) 85.

    Google Scholar 

  70. 70

    Kolinska, J. and Semenza, G., Biochim. Biophys. Acta, 146 (1967) 181.

    Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Gary S. Jacob.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jacob, G.S., Bryant, M.L. Iminosugar glycosylation inhibitors as anti-HIV agents. Perspectives in Drug Discovery and Design 1, 211–224 (1993). https://doi.org/10.1007/BF02171663

Download citation

Key words

  • N-butyl-deoxynojirimycin
  • α-Glucosidase inhibitors
  • Anti-HIV prodrug