Skip to main content
SpringerLink
Log in

Crystal structures of HIV-1 protease-inhibitor complexes

  • Perspectives
  • Published:
Perspectives in Drug Discovery and Design

Summary

HIV PR is one of the most popular targets for the development of drugs for treatment of AIDS and in the last few years, a significant effort has been directed towards its structure elucidation in both liganded and unliganded form. In this review, 25 available crystal structures of HIV PR complexes with inhibitors are described. Binding of peptidic inhibitors to the HIV PR active site are analyzed in view of the formation of potential hydrogen bonds and filling of hydrophobic space. A potential impact of the accumulated crystallographic effort on the development of computational methods for structure-based drug design is briefly addressed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Mitsuya, H., Yarchoan, R. and Broder, S., Science, 249 (1990) 1533.

    Google Scholar 

  2. Tomasselli, A.G., Howe, J.W., Sawyer, T.K., Wlodawer, A. and Heinrikson, R.L., Chimica Oggi, 9 (1991) 6.

    Google Scholar 

  3. Kohl, N.E., Emini, E.A., Schleif, W.A., Davis, L.J., Heimbach, J.C., Dixon, R.A.F., Scolnick, E.M. and Sigal, I.S., Proc. Natl. Acad. Sci. USA, 85 (1988) 4186.

    Google Scholar 

  4. McQuade, T.K., Tomasselli, A.G., Liu, L., Karacostas, V., Moss, B., Sawyer, T.K., Heinrikson, R.L. and Tarpley, W.G., Science, 247 (1990) 454.

    Google Scholar 

  5. Toh, H., Ono, M., Saigo, K. and Miyata, T., Nature, 315 (1985) 691.

    Google Scholar 

  6. Krausslich, H.G., Ingraham, R.H., Skoog, M.T., Wimmer, E., Pallai, P.V. and Carter, C.A., Proc. Natl. Acad. Sci. USA, 86 (1989) 807.

    Google Scholar 

  7. Heimbach, J.C., Garsky, V.M., Michelson, S.R., Dixon, R.A.F., Sigal, I.S. and Darke, P.L., Biochem. Biophys. Res. Commun., 164 (1989) 955.

    Google Scholar 

  8. Schneider, J. and Kent, S.B.H., Cell, 54 (1988) 363.

    Google Scholar 

  9. Wlodawer, A. and Erickson, J.W., Annu. Rev. Biochem., 62 (1993) 543.

    Google Scholar 

  10. Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Selk, L., Kent, S.B.H. and Wlodawer, A., Science, 246 (1989) 1149.

    Google Scholar 

  11. Swain, A.L., Miller, M., Green, J., Rich, D.H., Schneider, J., Kent, S.B.H. and Wlodawer, A., Proc. Natl. Acad. Sci. USA, 87 (1990) 8805.

    Google Scholar 

  12. Jaskolski, M., Tomasselli, A.G., Sawyer, T.K., Staples, R.L., Heinrikson, R.L., Schneider, J., Kent, S.B.H. and Wlodawer, A., Biochemistry, 30 (1991) 1600.

    Google Scholar 

  13. Erickson, J.W., Neidhardt, D.J., VanDrie, J., Kempf, D.J., Wang, X.C., Norbeck, D.W., Plattner, J.J., Rittenhouse, J.W., Turon, M., Wideburg, N., Kohlbrenner, W.E., Simmer, R., Helfrich, R., Paul, D.A. and Knigge, M., Science, 249 (1990) 527.

    Google Scholar 

  14. Fitzgerald, P.M.D., McKeever, B.M., VanMiddleworth, J.F., Springer, J.P., Heimbach, J.C., Leu, C.-T., Herber, W.K., Dixon, R.A.F. and Darke, P.L., J. Biol. Chem., 265 (1990) 14209.

    Google Scholar 

  15. Graves, B.J., Hatada, M.H., Miller, J.K., Graves, M.C., Roy, S., Cook, C.M., Krohn, A., Martin, J.A. and Roberts, N.A., In Dunn, B. (Ed.) Structure and Function of the Aspartic Proteinases, Plenum Press, New York, 1992, pp. 455–460.

    Google Scholar 

  16. Bone, R., Vacca, J.P., Anderson, P.S. and Holloway, M.K., J. Am. Chem. Soc., 113 (1991) 9382.

    Google Scholar 

  17. Krohn, A., Redshaw, S., Ritchie, J.C. and Hatada, M.H., J. Med. Chem., 34 (1991) 3340.

    Google Scholar 

  18. Dreyer, G.B., Lambert, D.M., Meek, T.D., Carr, T.J., Tomaszek, T.A., Fernandez, A.V., Bartus, H., Cacciavillani, E., Hassel, A.M., Minnich, M., Petteway Jr., S.R., Metcalf, B.W. and Lewis, M., Biochemistry, 31 (1992) 6646.

    Google Scholar 

  19. Thanki, N., Rao, J.K.M., Foundling, S.I., Howe, W.J., Moon, J.B., Tomasselli, A.G., Heinrikson, R.L., Thaisrivongs, S. and Wlodawer, A., Protein Sci., 1 (1992) 1061.

    Google Scholar 

  20. Thompson, W.J., Fitzgerald, P.M.D., Holloway, M.K., Emini, E.A., Darke, P.L., Keever, B.M., Schleif, W.A., Quintero, J.C., Zugay, J.A., Tucker, T.J., Schwering, J.E., Homnick, C.F., Nunberg, J., Springer, J.P. and Huff, J.R., J. Med. Chem., 35 (1992) 1685.

    Google Scholar 

  21. Humber, D.C., Cobley, K.N., Evans, D.N., Storer, R., Weingarten, G.G., Hann, M.M., Mistry, A., Wonacott, A., Cammack, N. and Orr, D.C., VIIIth International Conference on AIDS, Amsterdam, 1992, POA 2280.

  22. Dreyer, B.G., Boehm, J.C., Chenera, B., DesJarlais, R.L., Hassel, A.M., Meek, T.D., Tomaszek, T.A. and Lewis, M., Biochemistry, 32 (1993) 937.

    Google Scholar 

  23. Pearl, L.N. and Taylor, W.R., Nature, 329 (1987) 351.

    Google Scholar 

  24. Miller, M., Jaskolski, M., Rao, J.K.M., Leis, J. and Wlodawer, A., Nature, 337 (1989) 576.

    Google Scholar 

  25. Navia, M.A., Fitzgerald, P.M.D., McKeever, B.M., Leu, C.-T., Heimbach, J.C., Herber, W.K., Sigal, I.S., Darke, P.L. and Springer, J.P., Nature, 337 (1989) 615.

    Google Scholar 

  26. Lapatto, R., Blundell, T., Hemmings, A., Overington, J., Wilderspin, A., Wood, S., Merson, J.R., Whittle, P.J., Danley, D.E., Geoghegan, K.F., Havrylik, S.J., Lee, S.E., Scheld, K.G. and Hobart, P.M., Nature, 342 (1989) 299.

    Google Scholar 

  27. Wlodawer, A., Miller, M., Jaskolski, M., Sathyanarayana, B.K., Baldwin, E., Weber, I.T., Selk, L.M., Clawson, L., Schneider, J. and Kent, S.B.H., Science, 245 (1989) 616.

    Google Scholar 

  28. Tang, J., James, M.N.G., Hsu, I.N., Jenkins, J.A. and Blundell, T., Nature, 271 (1978) 618.

    Google Scholar 

  29. Meek, T.D., Lambert, B.W., Metcalf, B.W., Petteway Jr., S.R. and Dreyer, G.B., In De Clercq, E. (Ed.) Design of Anti-AIDS Drugs, Elsevier, Amsterdam, 1990, p. 225.

    Google Scholar 

  30. Blundell, T., Jenkins, J.A., Pearl, L.H., Sewell, T. and Pedersen, V., In Kostka, V. (Ed.) Aspartic Proteinases and Their Inhibitors, De Gruyter, Berlin, 1985, pp. 151–161.

    Google Scholar 

  31. James, M.N.G. and Sielecki, A., J. Mol. Biol., 163 (1983) 299.

    Google Scholar 

  32. Schechter, I. and Berger, A., Biochem. Biophys. Res. Commun., 27 (1967) 157.

    Google Scholar 

  33. Wlodawer, A., Nachman, J., Gilliland, G.L., Gallagher, W. and Woodward, C., J. Mol. Biol., 198 (1987) 469.

    Google Scholar 

  34. Lewis, P.N., Momany, F.A. and Scheraga, H.A., Proc. Natl. Acad. Sci. USA, 68, (1971) 2293.

    Google Scholar 

  35. Swain, A.L., Gustchina, A. and Wlodawer, A., In Dunn, B. (Ed.) Structure and Function of the Aspartic Proteinase: Genetics, Structure and Mechanism, Plenum Press, New York, NY, 1992, pp. 433–441.

    Google Scholar 

  36. Thaisrivongs, S., Pals, D.T., Kroll, L.T., Turner, S.R. and Han, F.-S., J. Med. Chem., 30 (1987) 976.

    Google Scholar 

  37. Taisrivongs, S., Tomasselli, A.G., Moon, J.B., Hui, J., McQuade, T.J., Turner, S.R., Strohbach, J.W., Howe, W.J., Tarpley, W.G. and Heinrikson, R.L., J. Med. Chem., 34 (1991) 2344.

    Google Scholar 

  38. Ryono, D.E., Free, C.A., Neubeck, R., Samaniego, S.G., Godfrey, J.D. and Petrillo Jr., E.W. In Deber, C.M., Hruby, V.J. and Kopple, K.D. (Eds.) Peptides, Structure and Function, Proceedings of the Ninth American Peptide Symposium, Pierce Chemical and Co, 1985, pp. 739–748.

  39. Dann, J.G., Stammers, D.K., Harris, C.J., Arrowsmith, R.J., Davies, D.E., Hardy, G.W. and Morton, J.A., Biochem. Biophys. Res. Commun., 134 (1986) 71.

    Google Scholar 

  40. Rich, D.H., Green, J., Toth, M.V., Marshall, G.R. and Kent, S.B.H., J. Med. Chem., 33 (1990) 1285.

    Google Scholar 

  41. Roberts, N.A., Martin, J.A., Kinchington, D., Broadhurst, A.V., Craig, J.C., Duncan, I.B., Galpin, S.A., Handa, B.K., Kay, J., Krohn, A., Lambert, R.W., Merrett, J.H., Mills, J.S., Parkes, K.E.B., Redshaw, S., Ritchie, A.J., Taylor, D.L., Thomas, G.J. and Machin, P.J., Science, 248 (1990) 358.

    Google Scholar 

  42. Rich, D.H., Sun, Ch.-Q., Vara Prasad, J.V.N., Pathiasseril, A., Toth, M.V., Marshall, G.R., Clare, M., Mueller, R.A. and Hauseman, K., J. Med. Chem., 34 (1991) 1222.

    Google Scholar 

  43. Huff, J.R., J. Med. Chem., 34 (1991) 2305.

    Google Scholar 

  44. VanDrie, J.H., Weininger, D. and Martin, Y.C., J. Comput.-Aided Mol. Design, 3 (1989) 225.

    Google Scholar 

  45. Kuntz, I.D., Blanley, J.M., Oatley, S.J., Langridge, R. and Ferrin, T.E., J. Mol. Biol., 161 (1982) 269.

    Google Scholar 

  46. Van Gunsteren, W.F. and Berendsen, H.J.C., Angew. Chem. Int. Ed. Eng., 29 (1990) 992.

    Google Scholar 

  47. Rami Reddy, M., Bacquet, R.J., Zichi, D., Matthews, D.A., Welsh, K.M., Jones, T.R. and Freer, S., J. Am. Chem. Soc., 114 (1992) 10117.

    Google Scholar 

  48. Rami Reddy, M., Viswanadhan, V.N. and Weinstein, J.N., Proc. Natl. Acad. Sci. USA, 88 (1991) 10287.

    Google Scholar 

  49. Rami Reddy, M., Varney, M., Kalish, V., Viswanadhan, V.N. and Appelt, K., submitted to Science.

  50. Fitzgerald, P,M.D., McKeever, B.M., VanMiddlesworth, J.F. and Springer, J.P., In Kumar, A. (Ed.) Advances in Molecular Biology and Targeted Treatment for AIDS, Plenum Press, New York, 1991, pp. 245–249.

    Google Scholar 

  51. Rutenber, E., Fauman, E.B., Keenan, R.J., Fong, S., Furth, P.S., Oritz de Montellano, P.R., Meng, E., Kuntz, I.D., DeCamp, D.L., Salto, R., Rose, J.R., Craik, C.S. and Stroud, R.M., J. Biol. Chem., 1993, in press.

  52. DesJarlais, R.L., Seibel, G.L., Kuntz, I.D., Furth, P.S., Alvarez, J.C., Ortiz de Montello, J.C., DeCamp, D.L., Babe, L.M. and Craik, C.S., Proc. Natl. Acad. Sci. USA, 87 (1990) 6644.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Agouron Pharmaceuticals Inc., 3565 General Atomics Court, 92121, San Diego, CA, USA

    Krzysztof Appelt

Authors
  1. Krzysztof Appelt
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Appelt, K. Crystal structures of HIV-1 protease-inhibitor complexes. Perspectives in Drug Discovery and Design 1, 23–48 (1993). https://doi.org/10.1007/BF02171654

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02171654

Key words

Search

Navigation