Rational design of inhibitors for drug-resistant HIV-1 aspartic protease mutants

Drug Design and Discovery

Volumn 15, Issue 4, 1998, Pages 211-231

  Frecer, Vladimir ^a,c   Miertus, Stanislav ^a,b   Tossi, Alessandro ^d   Romeo, Domenico ^d  

^a POLYtech   (Italy)

^b UNIDO   (Italy)

^c CANCER RESEARCH INSTITUTE   (Slovakia)

^d UNIVERSITY OF TRIESTE   (Italy)

Author keywords

Aspartic protease; Drug resistance; HIV 1; Pseudopeptide inhibitors

Indexed keywords

A 77003; ASPARTIC PROTEINASE; ENZYME INHIBITOR; SOLVENT;

ARTICLE; BINDING AFFINITY; BIOAVAILABILITY; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG RESISTANCE; HUMAN IMMUNODEFICIENCY VIRUS 1; HYDROPHILICITY; LIGAND BINDING; MOLECULAR MODEL; THERMODYNAMICS; VIRUS MUTANT;

EID: 84962426043     PISSN: 10559612     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (68)

1. Kuntz, I.D. (1992) Structure-based strategies for drug design and discovery. Science, 257, 1078-1082.
2. Debouck, C. (1992) The HIV-1 protease as therapeutic target for AIDS. AIDS Res. Hum. Retroviruses, 8, 153-164.
3. Wlodawer, A. and Erickson, J.W. (1993) Structure-based inhibitors of HIV-1 protease. Annu. Rev. Biochem., 62, 543-585.
4. Abdel-Meguid, S.S. (1993) Inhibitors of aspartyl proteinases. Med. Res. Rev., 13, 731-778
5. De Clercq. E. (1995) Toward improved anti-HIV chemotherapy, therapeutic strategies for intervention with HIV infections. J. Med Chem , 38, 2491-2517.
6. West, M.L. and Fairlie, D.P. (1995) Targeting HIV-1 protease: a test of drug-design methodologies Trends Pharm. Sci., 16, 67-75.
7. Fox, J.L. (1996) Two more HIV protease inhibitors approved. Nature Biotech., 14, 427.
8. Roberts, N.A., Martin, J.A., Kinchinglon, 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, AJ., Taylor, D.L., Thomas, G.J. and Machin, P.J. (1990) Rational design of peptide-based HIV protemase inhibitors. Science, 248, 358-361.
9. Kempf, D.J., Marsh, K.C., Denissen, J.F., McDonald, E., Vasavanonda, S.A., Flentge, C., Green, B G , Fino. L., Park, C.H., Kong, X.P., Wideburg, N.E., Saldivar, A., Ruiz, L., Kati, W M., Sham, H.L., Robins, T., Stcwart, K.D., Hsu, A., Plattner, J.J., Leonard, J.M. and Norbeck, D.W. (1995) ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has oral bioavailability in humans. Proc. Natl. Acad. Sci. USA, 92, 2484-2488.
10. Vacca, J.P., Dorsey, B.D., Schlief, W.A., Levin, R.B., McDaniel, S.L., Darke. P.L , Zugay, J., Quintero, J.C., Blahy, O M., Roth. E., Sardana, V.V., Schalbach, A.J., Graham, P.L, Condra, J H., Gotlib, L., Holloway, M.K., Lin, J., Chen, I.W., Vastag, K., Ostovic, D., Anderson, P.S , Emini, E.A. and Huff, J.R (1994) L-735.524: An orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc. Natl. Acad. Sci. USA, 91, 4096-4100.
11. Ho, D.D., Neuman, A U., Perelson, A.S., Chen, W., Leonard, J.M. and Markowitz, M. (1995) Rapid turnover of plasma virions and CD4 lymphocytes in HIV-I infection Nature, 373, 123-126.
12. Condra, J.H., Schleif, W.A., Blahy, O M., Gabryelski, L.J., Graham, D.J., Quintero, J.C., Rhodes, A., Robins, H.L., Roth, E., Shivaprakash, M., Titus, D., Yang, T., Teppler, H., Squires, K., Deutsch, P and Emini, E. (1995) In vivo emergence of HIV-I variants resistant to multiple protease inhibitors. Nature, 374. 569-571
13. Otto, M.J., Garber, S., Winslow, D L., Reid, C D , Aldrich, P., Jadhav, P.K., Patterson, C.E., Hodge, C.N. and Cheng, Y -S (1993) In vitro isolation and identification of human immunodeficiency virus (HIV) variants with reduced sensitivity to C-2 symmetrical inhibitors of HIV Type 1 protease. Proc. Natl. Acad. Sci. USA, 90, 7543-7547.
14. Kaplan, A.H., Michael, S F., Wehbie, R.S., Knigge, M.F., Paul, D.A., Everitt, L., Kempf. D.J , Norbeck, D.W., Erickson, J.W. and Swanstrom, R. (1994) Selection of multiple human immunodeficiency virus Type 1 variants that encode viral proteases with decreased sensitivity to an inhibitor of the viral protease. Proc. Natl. Acad. Sci. USA, 91, 5597-5601.
15. El-Farrash, M.A., Kuroda, M J , Kitazaki, T., Masuda, T., Kato, K., Hatanaka, M. and Harada, S. (1994) Generation and characterization of a human immunodeficiency virus Type 1 (HIV-1) mutanl resistant to an HIV-1 protease inhibitor. J. Virol., 68, 233-239.
16. Coffin, J.M. (1995) HIV population dynamics in vivo: implications for genetic variation, pathogenesis and therapy. Science, 267, 483-489.
17. Chen, Z., Li, Y , Schock. H.B., Hall, D., Chen, E. and Kuo, L.C. (1995) Three-dimensional structure of a mutant HIV-1 protease displaying cross-resistance to all protease inhibitors in clinical trials. J. Biol. Chem., 270, 21433-21436.
18. Ridky, T. and Leis. J. (1995) Development of drug resistance to HIV-1 protease inhibitors. J. Biol. Chem., 270, 29621-29623
19. Rose, R.E., Gong, Y.F., Greylok, J.A., Bechtold, C.M., Terry, B.J., Robinson, B.S., Alam, M., Colonno, R.J. and Lin, P.F. (1996) Human immunodeficiency virus Type 1 viral background plays a major role in development of resistance to protease inhibitors. Proc. Natl. Acad. Sci. USA, 93, 1648-1653.
20. Cameron, C.E., Ridky, T.W., Shulenin, S., Leis, J., Weber, I.T., Copeland, T., Wlodawer, A , Burstein, H., Bizub-Bender, D. and Skalka, A.M. (1994) Mutational analysis of the substrate binding pockets of the TOUS sarcoma virus and human immunodeficiency Virus-1 proteases. J. Biol. Chem., 269, 11170-11177.
21. Cameron, C.E., Grinde, B., Jacques, P., Jentoft, J., Leis, J., Wlodawer, A. and Weber, I.T. (1993) Comparison of the substrate-binding pockets of the Rous Sarcoma Virus and human immunodeficiency virus Type 1 proteases. J. Biol. Chem., 268, 11711-11720.
22. Gulnik, S.V., Suvorov, L.I., Liu, B., Yu, B., Anderson, B., Mitsuya, H and Erickson, J.W. (1995) Kinetic characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug pressure. Biochemistry, 34, 9282-9287.
23. Baldwin, E.T., Bhat, T.N., Liu, B., Pattabiraman, N. and Erickson, J.W. (1995) Structural basis of drug resistance for the V82A mutant of HIV-1 proteinase. Nature Struct. Biol., 2, 244-249, Protein Data Bank entry ID code: 1hvs.
24. Loftus, R. and Gold, D. (1995) Protease inhibitors: where are they now? GMHC Newdet. Exp. AIDS Ther., 9, 1-7.
25. Richman, D.D (1993) HIV drug resistance. Annu. Rev. Pharmacol. Toxicol., 32, 149-164.
26. Miertus, S., Scrocco, E. and Tomasi, J. (1981) Electrostatic interaction of a solute with a continuum. A direct utilization of ab initio molecular potentials for the prevision of solvent effects. Chem. Phys., 55, 117-129.
27. Frecer, V. and Miertus, S. (1992) Polanzable continuum model of solvation for biopolymers. Int. J. Quant. Chem., 42, 1449-1468.
28. Miertus, S. and Frecer, V. (1992) Continuum models of environmental effects on molecular structure and mechanisms in chemistry and biology, J. Math. Chem., 10, 183-204.
29. Miertus, S., Frecer, V. and Majekova, M. (1990) Environmental effects in the molecular mechanisms of action of bioactive compounds. In Theoretical Biochemistry and Biophysics; A Comprehensive Survey. Edited by D.L. Beveridge, R.L. Lavery, pp. 131-142. New York. Adenine Press
30. Miertus, S. and Frecer. V. (1993) Evaluation of solvent effects on complexation between AP of HIV-1 and its inhibitors. In Water- Biomolecule Interactions, edited by M.U Palma, M.B. Palma, F. Parak, pp. 195-200. Bologna. SIF.
31. Miertus, S. (1993) Evaluation of eomplexation energies between aspartic protease of HIV-1 and its hexapeptide inhibitors including the effect of solvation. Bioorg. Med. Chem Letters, 3, 2105-2112.
32. Miertus, S., Antcheva, N., Tossi, A., Bizik, F., Benedetti, F., Gennaro, R. and Romeo, D. (1995) CADD of new pseudo-peptide inhibitors of HIV-1 aspartic protease. In QSAR and Molecular Modelling: Concepts. Computational Tools and Biological Applications. Edited by F. Sanz, J Giraldo, F Manaut, pp. 579-582. Barcelona: Prous Science Publishers.
33. Tossi, A., Antcheva, N , Romeo, D. and Miertus, S. (1995) Development of pseudopeptide inhibitors of HlV-1 aspartic protease. analysis and tuning of the subsite specificity. Peptide Res., 8, 2-8.
34. Miertus. S , Furlan, M., Tossi, A. and Romeo, D. (1996) Design of new inhibitors of HIV-1 aspartic protease Chem Phys., 204, 173-180.
35. (a) Ferguson, D.M., Radmer, R.J. and Kollman, P.A. (1991) Determination of the relative binding free energies of peptide inhibitors to the HIV-1 protease. J. Med. Chem., 34, 2654-2659;
36. (b) Rao, B.G., Tilton, R.F. and Singh, U.C. (1992) Free energy perturbation studies oil inhibitor binding to HIV-1 proteinase. J. Am. Chem. Soc , 114, 4447-4452
37. (c) Harte, W.E. Jr., Swaminathan, S. and Beveridge, D.L. (1992) Molecular dynamics of HIV-1 protease. Proteins: Struct. Func. Gen., 13, 175-194
38. (d) Chatfield, D.C. and Brooks, B.R. (1995) HIV-1 protease cleavage mechanism elucidated with molecular dynamics simulation. J. Am. Chem. Soc., 117, 5561-5572
39. (e) Chen, X. and Tropsha, A. (1995) Relative binding free energies of peptide inhibitors of HIV-1 protease: the influence of the active site protonation state. J. Med. Chem., 38, 42-48.
40. (f) Holloway, M.K., Wai, J.M., Halgren, T.A , Fitzgerald, P.M.D., Vacca, J.P., Dorsey, B.D., Levin, R.B., Thompson, W.J., Chen, L.J., deSolms, S.J., Gaffin, N., Ghosh, A.K., Giuliani, E.A , Graham, S.L., Guare, J.P., Hungate, R.W., Lyle, T.A., Sanders, W.M., Tucker, T.J., Wiggins. M., Wiscount, C.M., Wohersdorf, O.W., Young, S.D., Darke, P.L. and Zugay, J.A. (1995) A priori prediction of activity for HIV-1 protease inhibitors employing energy minimization in the active site. J. Med. Chem., 38, 305-317,
41. (g) Viswanadhan, V.N., Reddy, M.R., Wlodawer, A., Vamey, M-D and Weinstein, J.N. (1996) An approach to rapid estimation of relative binding affinities of enzyme inhibitors: application to peptidomimetic inhibitors of the human immunodeficiency virus Type 1 protease. J. Med. Chem., 39, 705-712;
42. (h) Ghosh, A.K , Kincaid, J.F., Walters, D E., Chen, Y., Chaudhuri, N.C., Thompson, W.J., Culberson, C , Fitzgerald, P.M.D., Lee, H.Y., McKee, S.P., Munson, P.M., Duong, T.T., Darke, P.L., Zugay, J.A , Schlief, W.A., Axel, M.G., Lin, J. and Huff, J.R. (1996) Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation. J. Med. Chem , 39, 3278-3290;
43. (i) Silva, A M., Cachau, R.E., Sham, H L. and Erickson, J.W. (1996) Inhibition and catalytic mechanism of HIV-1 aspartic protease. J. Mol. Biol., 255, 321-340
44. Wang, S.M., Milne, G.W.A., Yan, X J , Posey, I.J., Nicklaus, M.C , Graham, L. and Rice, W.G. (1996) Discovery of novel, non-peptide HIV-1 protease inhibitors by pharmacophore searching. J. Med. Chem., 39, 2047-2054.
45. 2 symmetric inhibitors of the human immunodeficiency virus Type 1 protease. Antimicrob. Agents Chemother., 35, 2209-2214
46. 2 symmetry-based diol inhibitors of HIV-1 protease. J. Am Chem. Soc., 116, 847-855, Protein Data Bank entry ID code: 1hvi.
47. R II User Guide (1995) Biosym/MSI, San Diego, CA.
48. Navia, M.A, Fitzgerald, P.M., McKeever, B.M , Leu. C.T., Heimbach, J.C., Herber, W.K., Sigal, I.S., Drake, P.L. and Springer, J.P. (1989) Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature, 337, 615-620, Protein Data Bank entry ID code' 2hvp.
49. Schechter, I. and Berger, A. (1967) On the size of the active site in proteases I Papain. Biochem. Biophys. Res. Commun., 27, 157-162.
50. Dauber-Osguthorpe, P., Roberts, V.A., Osguthorpe, D.J., Wolff, J., Genest, M. and Hagler, A.T. (1988) Structure and energetics of hgand binding to proteins: E Coli Dihydrofolate Reductase-Trimethoprim, a drug-receptor system. Proreins. Struc. Fun. Gen., 4, 31-47
51. McQuarrie, D.A. (1976) Statistical Thermodynamics, New York: Harper & Row.
52. Hagler, A.T., Stern, P.S., Sharon, R., Backer, J.M. and Naider, F. (1979) Computer simulation of the conformational properties of oligopeptides. Comparison of theoretical methods and analysis of experimental results. J. Am. Chem. Soc., 101, 6842-6852.
53. 2-symmetric protease inhibitor. J. Virol, 68, 2016-2020.
54. Wang, Y X., Freedberg, D.I., Yarnazaki, T., Wingfield, P.T., Stahl, S.J., Kaufman, J.D., Kiso, Y. and Torchia, D.A. (1996) Solution NMR evidence that the HIV-1 protease catalytic aspartyl groups have different ionization states in the complex formed with the asymmetric drug KNI-272. Biochemistry, 35, 9945-9950.
55. Connolly, M.L. (1983) Solvent-accessible surfaces of proteins and nucleic acids. Science, 221, 709-713.
56. Rekker, R.F. and Manhold, R. (1992) Calculation of Drug Lipophilicity, Wemheim: VCH Publishers.
57. (a) Hansch, C. and Leo, A.J. (1979) Substituent Constants for Correlation Analysis in Chenustry and Biology. New York: J. Wiley.
58. (b) Leo, A.J and Weininger, D. (1991) CLOGP, Daylight Chemical Information Systems, Irvine, CA.
59. Mannhold, R., Rekker, R.F., Sonntag, C., Ter Laak, A.M., Dross, K. and Polymeropoulos, E.E. (1995) Comparative evaluation of the predictive power of calculation procedures for molecular lipophilicity. J. Pharm. Sci., 84, 1410-1419.
60. Meylan, WM and Howard, P.H. (1995) Atom/fragment contribution method for estimation octanol-water partition coefficients. J. Pharm. Sci , 84, 83-92.
61. (a) Miertus, S., Trebaticka, M , Frecer, V. and Jakus, V. (1985) Theoretical study on interphase partitioning and its use in QSAR analyses In QSAR in Toxicology and Xenobiochemistry. Edited by M. Tichy, pp 214-220. Amsterdam: Elsevier.
62. (b) Miertus, S., Jakus, V. and Matisova, E. (1990) Theoretical interpretation of the retention indices of Alkylbenzenes. Chromatographia. 30, 144-151.
63. Korant, B., Lu, Z., Strack, P. and Rizzo. C. (1996) HIV Protease mutations leading to reduced inhibitor susceptibility. In Intracellular Protein Catabolism Edited by K Suzuki, J Bond, pp. 241-245. New York: Plenum Press.
64. (a) Plattner, J J. and Norbeck, D.W (1990) Chapter 5. Obstacles to drug development from peptide leads. In Drug Discovery Technologies. Edited by C.R. Clark, W.H. Moos, pp. 92-126. Chichester. Ellis Horwood,
65. (b) Olson, G.L , Bohn, D.R., Bonner, M.P., Bös, M., Cook, C.M , Fry, D.C., Graves, B.J., Hatada, M., Hill, D.E., Kahn. M., Madison, V.S., Rusiecki, V.K., Sarabu, R., Sepinwall, J., Vincent, O.P. and Voss, M.E (1993) Concepts and progress in the development of peptide mimetics. J. Med. Chem., 36, 3039-3049.
66. Romines, K.R., Watenpauah, K.D., Tomich, P.K., Howe, W J., Morris, J.K., Lovasz, K.D., Mulichak, A.M., Finzel, B.C., Lynn, J.C., Honig, M.M., Schwende, F.J., Ruwart, M.J., Gail, L.Z., Chong, K T., Dolak, L.A., Toth, L.N., Howard, G.M., Rush, B.D., Wilkinson, K.F., Possen, P.L., Dalga, R.J and Hinshaw, R.R (1995) Use of medium-sized cycloaikyl rings to enhance secondary binding: discovery of a new class of human immunodeficiency virus (HIV) protease inhibitors, J Med. Chem., 38, 1884-1891.
67. Young, S.D., Payne, L.S., Thompson. W.I., Gaffin, N., Lyle, T.A , Brichter, S.F., Graham, S.L., Schultz, T.H., Deana, A.A., Darke, P.L., Zugay, J., Schleif, W A., Quintero, J.C., Emini, E.A., Anderson, P.S. and Huff, J.R. (1992) HIV-1 protease inhibitors based on hydroxyethylene dipeptide isosteres' an investigation into the role of the P1' side chain on structure-activity, J. Med. Chem., 35, 1702-1709.
68. Lehr, P , Billich, A., Charpiot, B., Ettmayer, P., Scholz, D., Rosenwirth, B. and Gstach, H. (1996) Inhibitors of human immunodeficiency virus Type 1 protease containing 2-Aminobenzyl-substituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: synthesis, activity, and oral bioavailability. J. Med. Chem., 39, 2060-2067.