Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors

European Journal of Biochemistry

Volumn 270, Issue 8, 2003, Pages 1746-1758

  Andersson, Hans O ^a   Fridborg, Kerstin ^a   Löwgren, Seved ^a   Alterman, Mathias ^a   Mühlman, Anna ^c   Björsne, Magnus ^c   Garg, Neeraj ^a   Kvarnström, Ingmar ^b   Schaal, Wesley ^a   Classon, Björn ^c   Karlén, Anders ^a   Danielsson, U Helena ^a   Ahlsén, Göran ^a   Nillroth, Ullrika ^a   Vrang, Lotta ^d   Öberg, Bo ^d   Samuelsson, Bertil ^c   Hallberg, Anders ^a   Unge, Torsten ^a  

^a UPPSALA UNIVERSITY   (Sweden)

^b LINKÖPING UNIVERSITY   (Sweden)

^c STOCKHOLM UNIVERSITY   (Sweden)

^d MEDIVIR AB   (Sweden)

Author keywords

AIDS; Drug; HIV; Protease; X ray

Indexed keywords

ASPARTIC ACID; HYDROXYL GROUP; OXYGEN; PROTEINASE; PROTEINASE INHIBITOR;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING AFFINITY; CATALYSIS; CONTROLLED STUDY; CRYSTAL STRUCTURE; CRYSTALLIZATION; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME ACTIVITY; ENZYME INHIBITION; ENZYME PURIFICATION; GENE EXPRESSION; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROGEN BOND; NONHUMAN; PRIORITY JOURNAL; STRUCTURE ANALYSIS;

AMINO ACID SEQUENCE; BINDING SITES; CRYSTALLOGRAPHY, X-RAY; DNA PRIMERS; HIV PROTEASE; HIV PROTEASE INHIBITORS; HIV-1; KINETICS; MODELS, MOLECULAR; PROTEIN CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP;

HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1; RNA VIRUSES;

EID: 0038409048     PISSN: 00142956     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1432-1033.2003.03533.x     Document Type: Article

References (57)

1. Kohl, N.E., Emini, E.A., Schleif, W.A., Davis, L.J., Heimbach, J.C., Dixon, R.A., Scolnick, E.M. & Sigal, I.S. (1988) Active human immunodeficiency virus protease is required for viral infectivity. Proc. Natl Acad. Sci. USA 85, 4686-4690.
2. Peng, C., Ho, B.K., Chang, T.W. & Chang, N.T. (1989) Role of human immunodeficiency virus type 1-specific protease in core protein maturation and viral infectivity. J. Virol. 63, 2550-2556.
3. Gottlinger, H.G., Sodroski, J.G. & Haseltine, W.A. (1989) Role of capsid precursor processing and myristoylation in morphogenesis and infectivity of human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 86, 5781-5785.
4. Debouck, C., Gorniak, J.G., Strickler, J.E., Meek, T.D., Metcalf, B.W. & Rosenberg, M. (1987) Human immunodeficiency virus protease expressed in Escherichia coli exhibits autoprocessing and specific maturation of the gag precursor. Proc. Natl Acad. Sci. USA 84, 8903-8906.
5. Graves, M.C., Lim, J.J., Heimer, E.P. & Kramer, R.A. (1988) An 11-kDa form of human immunodeficiency virus protease expressed in Escherichia coli is sufficient for enzymatic activity. Proc. Natl Acad. Sci. USA 85, 2449-2453.
6. Hansen, J., Billich, S., Schulze, T., Sukrow, S. & Moelling, K. (1988) Partial purification and substrate analysis of bacterially expressed HIV protease by means of monoclonal antibody. EMBO J. 7, 1785-1791.
7. Debouck, C. (1992) The HIV-1 protease as a therapeutic target for AIDS. AIDS Res. Hum. Retroviruses 8, 153-164.
8. Wlodawer, A. & Vondrasek, J. (1998) Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu. Rev. Biophys. Biomol. Struct. 27, 249-284.
9. Bishofberger, N. & Öberg, B. (1999) Antivirals (HIV) editorial overview. Curr. Opin. Anti-Infect. Invest. Drugs 1, 125-126.
10. Richman, D.D. (2001) HIV chemotherapy. Nature (london) 410, 995-1001.
11. Carr, A. & Cooper, D.A. (1998) Images in clinical medicine. Lipodystrophy associated with an HIV-protease inhibitor. N. Engl. J. Med. 339, 1296.
12. Ridky, T. & Leis, J. (1995) Development of drug resistance to HIV-1 protease inhibitors. J. Biol. Chem. 270, 29621-29623.
13. Wlodawer, A., Miller, M., Jaskolski, M., Sathyanarayana, B.K., Baldwin, E., Weber, I.T., Selk, L.M., Clawson, L., Schneider, J. & Kent, S.B. (1989) Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 245, 616-621.
14. Navia, M.A., Fitzgerald, P.M., McKeever, B.M., Leu, C.T., Heimbach, J.C., Herber, W.K., Sigal, I.S., Darke, P.L. & Springer, J.P. (1989) Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature (London) 337, 615-620.
15. Schechter, I. & Berger, A. (1967) On the size of the active site in proteases. I. Papain. Biochem. Biophys. Res. Commun. 27, 157-162.
16. Wlodawer, A. & Erickson, J.W. (1993) Structure-based inhibitors of HIV-1 protease. Annu. Rev. Biochem. 62, 543-585.
17. Kempf, D.J., Norbeck, D.W., Codacovi, L., Wang, X.C., Kohlbrenner, W.E., Wideburg, N.E., Paul, D.A., Knigge, M.F., Vasavanonda, S., Craig-Kennard, A. et al. (1990) Structure-based, C2 symmetric inhibitors of HIV protease. J. Med. Chem. 33, 2687-2689.
18. Erickson, J., Neidhart, D.J., VanDrie, J., Kempf, D.J., Wang, X.C., Norbeck, D.W., Plattner, J.J., Rittenhouse, J.W., Turon, M., Wideburg, N. et al. (1990) Design, activity, and 2.8 Å crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. Science 249, 527-533.
19. Erickson, J. & Kempf, D. (1994) Structure-based design of symmetric inhibitors of HIV-1 protease. Arch. Virol. Suppl. 9, 19-29.
20. Kempf, D.J. (1994) Design of symmetry-based, peptidomimetic inhibitors of human immunodeficiency virus protease. Methods Enzymol. 241, 334-354.
21. Ho, D.D., Toyoshima, T., Mo, H., Kempf, D.J., Norbeck, D., Chen, C.M., Wideburg, N.E., Burt, S.K., Erickson, J.W. & Singh, M.K. (1994) Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor. J. Virol. 68, 2016-2020.
22. Mahalingam, B., Louis, J.M., Reed, C.C., Adomat, J.M., Krouse, J., Wang, Y.F., Harrison, R.W. & Weber, I.T. (1999) Structural and kinetic analysis of drug resistant mutants of HIV-1 protease. Eur. J. Biochem. 263, 238-245.
23. Weber, J., Mesters, J.R., Lepsik, M., Prejdova, J., Svec, M., Sponarova, J., Mlcochova, P., Skalicka, K., Strisovsky, K., Uhlikova, T., Soucek, M., Machala, L., Stankova, M., Vondrasek, J., Klimkait, T., Kraeusslich, H.G., Hilgenfeld, R. & Konvalinka, J. (2002) Unusual binding mode of an HIV-1 protease inhibitor explains its potency against multi-drug-resistant virus strains. J. Mol. Biol. 324, 739-754.
24. Yoshimura, K., Kato, R., Kavlick, M.F., Nguyen, A., Maroun, V., Maeda, K., Hussain, K.A., Ghosh, A.K., Gulnik, S.V., Erickson, J.W. & Mitsuya, H. (2002) A potent human immunodeficiency virus type 1 protease inhibitor, UIC- 94003 (TMC-126), and selection of a novel (A28S) mutation in the protease active site. J. Virol. 76, 1349-1358.
25. Hidaka, K., Kimura, T., Hayashi, Y., McDaniel, K.F., Dekhtyar, T., Colletti, L. & Kiso, Y. (2003) Design and synthesis of pseudosymmetric HIV protease inhibitors containing a novel hydroxymethylcarbonyl (HMC)-hydrazide isostere. Bioorg. Med. Chem. Lett. 13, 93-96.
26. Alterman, M., Bjorsne, M., Muhlman, A., Classon, B., Kvarnstrom, I., Danielson, H., Markgren, P.O., Nillroth, U., Unge, T., Hallberg, A. & Samuelsson, B. (1998) Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of 1-mannaric acid as a peptidomimetic scaffold. J. Med. Chem. 41, 3782-3792.
27. Alterman, M., Andersson, H.O., Garg, N., Ahlsen, G., Lovgren, S., Classon, B., Danielson, U.H., Kvarnstrom, I., Vrang, L., Unge, T., Samuelsson, B. & Hallberg, A. (1999) Design and fast synthesis of C-terminal duplicated potent C(2)-symmetric P1/P1′-modified HIV-1 protease inhibitors. J. Med. Chem. 42, 3835-3844.
28. Nillroth, U., Vrang, L., Markgren, P.O., Hulten, J., Hallberg, A. & Danielson, U.H. (1997) Human immunodeficiency virus type 1 proteinase resistance to symmetric cyclic urea inhibitor analogs. Antimicrob. Agents Chemother. 41, 2383-2388.
29. Weislow, O.S., Kiser, R., Fine, D.L., Bader, J., Shoemaker, R.H. & Boyd, M.R. (1989) New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS: antiviral activity. J. Natl Cancer Inst. 81, 577-586.
30. Otwinowski, Z. & Minor, W. (1997) Processing of x-ray diffraction data collected in oscillation mode. Methods Enzymol. 276, 307-326.
31. Gewirth, D. & Otwinowski, Z. (1995) The SCALEPACK Manual, available from http://www.dl.ac.uk/SRS/PX/jwc_external/abs_denzo_suite.html
32. Brünger, A.T., Adams, P.D., Clore, G.M., Delano, W.L., Gros, P., Grosse-Kunstleve, R.W., Jiang, J.-S., Kuszewski, J., Nilges, N., Pannu, N.S., Read, R.J., Rice, L.M., Simonson, T. & Warren, G.L. (1998) Crystallography and NMR system (CNS): a new software system for macromolecular structure determination. Acta Crystallogr. D54, 905-921.
33. Jones, T.A., Zou, J.-Y., Cowan, S.W. & Kjeldgaard, M. (1991) Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A. 47, 110-119.
34. Brünger, A.T., Kuriyan, J. & Karplus, M. (1987) Crystallographic R factor refinement by molecular dynamics. Science 235, 458-460.
35. Kleywegt, G.J. & Brünger, A.T. (1996) Checking your imagination: applications of the free R. value. Structure 4, 897-904.
36. Guex, N. & Peitsch, M.C. (1997) SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18, 2714-2723.
37. Vondrasek, J., van Buskirk, C.P. & Wlodawer, A. (1997) Database of three-dimensional structures of HIV proteinases. Nat. Struct. Biol. 4, 8.
38. Wlodawer, A. & Gustchina, A. (2000) Structural and biochemical studies of retroviral proteases. Biochim. Biophys. Acta 1477, 16-34.
39. Silva, A.M., Cachau, R.E., Sham, H.L. & Erickson, J.W. (1996) Inhibition and catalytic mechanism of HIV-1 aspartic protease. J. Mol. Biol. 255, 321-346.
40. Dreyer, G.B., Boehm, J.C., Chenara, B., DesJarlais, R.L., Hassell, A.M., Meek, T.D., Tomaszek, T.A. Jr & Lewis, M. (1993) A symmetric inhibitor binds HIV-1 protease asymmetrically. Biochemistry 32, 937-947.
41. 2 symmetry. J. Am. Chem. Soc. 113, 9382-9384.
42. Turner, B.G. & Summers, M.F. (1999) Structural biology of HIV. J. Mol. Biol. 285, 1-32.
43. Mager, P.P. (2001) The active site of HIV-1 protease. Med. Res. Rev. 21, 348-353.
44. Ren, S. & Lien, E.J. (2001) Development of HIV protease inhibitors: a survey. Prog. Drug Res. Spec. No 1-34.
45. Ala, P.J., DeLoskey, R.J., Huston, E.E., Jadhav, P.K., Lam, P.Y., Eyermann, C.J., Hodge, C.N., Schadt, M.C., Lewandowski, F.A., Weber, P.C., McCabe, D.D., Duke, J.L. & Chang, C.H. (1998) Molecular recognition of cyclic urea HIV-1 protease inhibitors. J. Biol. Chem. 273, 12325-12331.
46. Alterman, M., Sjobom, H., Safsten, P., Markgren, P.O., Danielson, U.H., Hamalainen, M., Lofas, S., Hulten, J., Classon, B., Samuelsson, B. & Hallberg, A. (2001) P1/P1′ modified HIV protease inhibitors as tools in two new sensitive surface plasmon resonance biosensor screening assays. Eur. J. Pharm. Sci. 13, 203-212.
47. Lam, P.Y.S., Jadhav, P.K., Eyermann, C.J., Hodge, C.N., Ru, Y., Bacheler, L.T., Meek, J.L., Otto, M.J., Rayner, M.M., Wong, Y.N., Chang, C.-H., Weber, P.C., Jackson, D.A., Sharpe, T.R. & Erickson-Viitanen, S. (1994) Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 263, 380-384.
48. Lam, P.Y., Ru, Y., Jadhav, P.K., Aldrich, P.E., DeLucca, G.V., Eyermann, C.J., Chang, C.H., Emmett, G., Holler, E.R., Daneker, W.F. et al. (1996) Cyclic HIV protease inhibitors: synthesis, conformational analysis, P2/P2′ structure-activity relationship, and molecular recognition of cyclic ureas. J. Med. Chem. 39, 3514-3525.
49. Hulten, J., Bonham, N.M., Nillroth, U., Hansson, T., Zuccarello, G., Bouzide, A., Aqvist, J., Classon, B., Danielson, U.H., Karlen, A., Kvarnstrom, I., Samuelsson, B. & Hallberg, A. (1997) Cyclic HIV-1 protease inhibitors derived from mannitol: synthesis, inhibitory potencies, and computational predictions of binding affinities. J. Med. Chem. 40, 885-897.
50. Hulten, J., Andersson, H.O., Schaal, W., Danielson, H.U., Classon, B., Kvarnstrom, I., Karlen, A., Unge, T., Samuelsson, B. & Hallberg, A. (1999) Inhibitors of the C(2)-symmetric HIV-1 protease: nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the P2/P2′ side chains. J. Med. Chem. 42, 4054-4061.
51. Wang, H. & Ben-Naim, A. (1996) A possible involvement of solvent-induced interactions in drug design. J. Med. Chem. 39, 1531-1539.
52. Mattos, C. (2002) Protein-water interactions in a dynamic world. Trends Biochem. Sci. 27, 203-208.
53. Bhat, T.N., Bentley, G.A., Boulot, G., Greene, M.I., Tello, D., Dall'Acqua, W., Souchon, H., Schwarz, F.P., Mariuzza, R.A. & Poljak, R.J. (1994) Bound water molecules and conformational stabilization help mediate an antigen-antibody association. Proc. Natl Acad. Sci. USA 91, 1089-1093.
54. Ladbury, J.E. (1996) Just add water! The effect of water on the specificity of protein-ligand binding sites and its potential application to drug design. Chem. Biol. 3, 973-980.
55. Engh, R.A. & Huber, R. (1991) Accurate bond and angle parameters for X-ray protein structure refinement. Acta Crystallogr. A 47, 392-400.
56. Kleywegt, G.J. & Jones, T.A. (1999) Software for handling macro molecular envelopes. Acta Crystallogr. D55, 941-944.
57. Kleywegt, G.J. & Jones, T.A. (1997) Detecting folding motifs and similarities in protein structures. Methods Enzymol. 277, 525-545.