Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: A new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains

Journal of Medicinal Chemistry

Volumn 48, Issue 24, 2005, Pages 7582-7591

  Himmel, Daniel M ^a   Das, Kalyan ^a   Clark Jr , Arthur D ^a   Hughes, Stephen H ^b   Benjahad, Abdellah ^c   Oumouch, Said ^c   Guillemont, Jérôme ^d   Coupa, Sophie ^d   Poncelet, Alain ^d   Csoka, Imre ^d   Meyer, Christophe ^d   Andries, Koen ^e   Nguyen, Chi Hung ^c   Grierson, David S ^c   Arnold, Eddy ^a  

^a RUTGERS UNIVERSITY   (United States)

^b NATIONAL CANCER INSTITUTE   (United States)

^c Laboratoire de Pharmacochimie   (France)

^d JOHNSON AND JOHNSON   (United States)

^e JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

6 BENZYL 1 [(BENZYLOXY)METHYL] 5 ISOPROPYLURACIL; ACRYLONITRILE; ASPARAGINE; CARBONYL DERIVATIVE; CYSTEINE; DAPIVIRINE; EMIVIRINE; ETRAVIRINE; FURAN; IODINE; LEUCINE; LYSINE; OXYGEN; PHENYLALANINE; PROLINE; PYRIDONE DERIVATIVE; R 157208; R 165481; R 221239; RILPIVIRINE; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR; TNK 651; TYROSINE; UNCLASSIFIED DRUG; VALINE; VIRUS ENZYME;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ARTICLE; COMPLEX FORMATION; CRYSTAL STRUCTURE; DRUG BINDING; DRUG EFFICACY; DRUG STRUCTURE; GENE MUTATION; HUMAN IMMUNODEFICIENCY VIRUS 1; NONHUMAN; STRUCTURE ACTIVITY RELATION;

CRYSTALLOGRAPHY, X-RAY; DRUG RESISTANCE, VIRAL; HIV-1; HIV-1 REVERSE TRANSCRIPTASE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; MUTATION; PYRIDONES; REVERSE TRANSCRIPTASE INHIBITORS;

EID: 28144445329     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0500323     Document Type: Article

References (56)

1. Retroviruses; Coffin, J. M., Hughes, S. H., Varmus, H. E., Eds.; Cold Spring Harbor Laboratory Press: Plainview, NY, 1997.
2. Kohlstaedt, L. A.; Wang, J.; Friedman, J. M.; Rice, P. A.; Steitz, T. A. Crystal Structure at 3.5 A Resolution of HIV-1 Reverse Transcriptase Complexed with an Inhibitor. Science 1992, 256, 1783-1790.
3. Jacobo-Molina, A.; Ding, J.; Nanni, R. G.; Clark, A. D., Jr.; Ju, X.; Tantillo, C.; Williams, R. L.; Kamer, G.; Ferris, A. L.; Clark, P.; Hizi, A.; Hughes, S. H.; Arnold, E. Crystal Structure of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Complexed with Double-Stranded DNA at 3.0 A Resolution Shows Bent DNA. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6320-6324.
4. Tantillo, C.; Ding, J.; Jacobo-Molina, A.; Nanni, R. G.; Boyer, P. L.; Hughes, S. H.; Pauwels, R.; Andries, K.; Janssen, P. A. J.; Arnold, E. Locations of Anti-AIDS Drug Binding Sites and Resistance Mutations in the Three-dimensional Structure of HIV-1 Reverse Transcriptase: Implications for Mechanisms of Drug Inhibition and Resistance. J. Mol. Biol. 1994, 243, 369-387.
5. Rodgers, D. W.; Camblin, S. J.; Harris, B. A.; Ray, S.; Culp, J. S.; Hellmig, B.; Woolf, D. J.; Debouck, C.; Harrison, S. C. The Structure of Unliganded Reverse Transcriptase from the Human Immunodeficiency Virus Type 1. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 1222-1226.
6. Das, K.; Ding, J.; Hsiou, Y.; Clark, A. D., Jr.; Moereels, H.; Koymans, L.; Andries, K.; Pauwels, R.; Janssen, P. A. J.; Boyer, P. L.; Clark, P.; Smith, R. H., Jr.; Smith, M. B. K.; Michejda, C. J.; Hughes, S. H.; Arnold, E. Crystal Structures of 8-Cl and 9-Cl TIBO Complexed with Wild-type HIV-1 RT and 8-Cl TIBO Complexed with the Tyr181Cys HIV-1 RT Drug-resistant Mutant. J. Mol. Biol. 1996, 264, 1085-1100.
7. Hsiou, Y.; Ding, J.; Das, K.; Clark, A. D., Jr.; Hughes, S. H.; Arnold, E. Structure of Unliganded HIV-1 Reverse Transcriptase at 2.7 A Resolution: Implications of Conformational Changes for Polymerization and Inhibition Mechanisms. Structure 1996, 4, 853-860.
8. Esnouf, R.; Ren, J.; Ross, C.; Jones, Y.; Stammers, D.; Stuart, D. I. Mechanism of Inhibition of HIV-1 Reverse Transcriptase by Non-nucleoside Inhibitors. Nat Struct. Biol. 1995, 2, 303-308.
9. Ding, J.; Das, K.; Hsiou, Y.; Zhang, W.; Arnold, E. Structural Studies of HIV-1 Reverse Transcriptase and Implications for Drug Design. In Structure-based Drug Design; Veerapandian, P., Ed.; Marcel Dekker: New York, 1997; pp 41-82.
10. Coffin, J. M. HIV Population Dynamics in Vivo: Implications for Genetic Variation, Pathogenesis, and Therapy. Science 1995, 267, 483-489.
11. De Clercq, E. Antiviral Therapy of Human Immunodeficiency Virus Infections. Clin. Microbiol. Rev. 1995, 8, 200-239.
12. Ho, D. D.; Neumann, A. U.; Perelson, A. S.; Chen, W.; Leonard, J. M.; Markowitz, M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995, 373, 123-126.
13. Arnold, E.; Das, K.; Ding, J.; Yadav, P. N. S.; Hsiou, Y.; Boyer, P. L.; Hughes, S. H. Targeting HIV Reverse Transcriptase for Anti-AIDS Drug Design. Drug Des. Discover 1996, 13, 29-47.
14. Sarafianos, S. G.; Das, K.; Hughes, S. H.; Arnold, E. Taking aim at a moving target: Designing drugs to inhibit drug-resistant HIV-I reverse transcriptases. Curr. Opin. Struct. Biol. 2004, 14, 716-730.
15. Ren, J.; Stammers, D. K. HIV reverse transcriptase structures: Designing new inhibitors and understanding mechanisms of drug resistance. Trends. Pharmacol. Sci. 2005, 26, 4-7.
16. Das, K.; Lewi, P. J.; Hughes, S. H.; Arnold, E. Crystallography and the design of anti-AIDS drugs: Conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog. Biophys. Mol. Biol. 2005, 88, 209-231.
17. Benjahad, A.; Guillemont, J.; Andries, K.; Nguyen, C. H.; Grierson, D. S. 3-iodo-4-phenoxypyridinones (IOPY's), a new family of highly potent non-nucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2003,13, 4309-4312.
18. Benjahad, A.; Courte, K.; Guillemont, J.; Mabire, D.; Coupa, S.; Poncelet, A.; Csoka, L; Andries, K.; Pauwels, R.; De Bethune, M. P.; Monneret, C.; Bisagni, E.; Nguyen, C. H.; Grierson, D. S. 4-Benzyl- and 4-benzoyl-3-dimethylaminopyridin-2(1H)-ones, a new family of potent anti-HIV agents: Optimization and in vitro evaluation against clinically important HIV mutant strains. J. Med. Chem. 2004, 47, 5501-5514.
19. Benjahad, A.; Croisy, M.; Monneret, C.; Bisagni, E.; Mabire, D.; Coupa, S.; Poncelet, A1; Csoka, I.; Guillemont, J.; Meyer, C.; Andries, K.; Pauwels, R.; De Bethune, M.-P.; Himmel, D. M.; Das, K.; Arnold, E.; Nguyen, C. H.; Grierson, D. S. 4-Benzyl and 4-Benzoyl-3-dimethylaminopyridin-2(1H)-ones: In vitro Evaluation of New C-3 Amino Substituted and C-5,6 Alkyl Substituted Analogues Against Clinically Important HIV Mutant Strains. J. Med. Chem. 2005, 48, 1948-1964.
20. Ding, J.; Das, K.; Hsiou, Y.; Sarafianos, S. G.; Clark, A. D.; Jr.; Jacobo-Molina, A.; Tantillo, C.; Hughes, S. H.; Arnold, E. Structure and Functional Implications of the Polymerase Active Site Region in a Complex of HIV-I RT with a Double-stranded DNA Template-primer and an Antibody Fab Fragment at 2.8 A Resolution. J. Mol. Biol. 1998, 284, 1095-1111.
21. Huang, H.; Chopra, R.; Verdine, G. L.; Harrison, S. C. Structure of a Covalently Trapped Catalytic Complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistance. Science 1998, 282, 1669-1675.
22. Sarafianos, S. G.; Das, K.; Tantillo, C.; Clark, A. D., Jr.; Ding, J.; Whitcomb, J. M.; Boyer, P. L.; Hughes, S. H.; Arnold, E. Crystal Structure of HIV-1 Reverse Transcriptase in Complex with a Polypurine Tract RNA:DNA. EMBO J. 2001, 20, 1449-1461.
23. Hopkins, A. L.; Ren, J.; Esnouf, R. M.; Willcox, B. E.; Jones, E. Y.; Ross, C.; Miyasaka, T.; Walker, R. T.; Tanaka, H.; Stammers, D. K.; Stuart, D. I. Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors. J. Med. Chem. 1996, 39, 1589-1600.
24. Ding, J.; Das, K.; Moereels, H.; Koymans, L.; Andries, K.; Janssen, P. A. J.; Hughes, S. H.; Arnold, E. Structure of HIV-1 RT/TIBO R 86183 Complex Reveals Similarity in the Binding of Diverse Non-nucleoside Inhibitors. Nat. Struct. Biol. 1995, 2, 407-415.
25. Jacques, P. S.; Wöhrl, B. M.; Ottmann, M.; Darlix, J.-L.; Le Grice, S. F. J. Mutating the "Primer Grip" of p66 HIV-1 Reverse Transcriptase Implicates Tryptophan-229 in Template-Primer Utilization. J. Biol. Chem. 1994, 269, 26472-26478.
26. Ghosh, M.; Jacques, P. S.; Rodgers, D. W.; Ottman, M.; Darlix, J.-L.; Le Grice, S. F. J. Alterations to the primer grip of p66 HIV-1 reverse transcriptase and their consequences for template-primer utilization. Biochemistry 1996, 35, 8553-8562.
27. Wöhrl, B. M.; Krebs, R.; Thrall, S. H.; Le Grice, S. F. J.; Axel J. Scheidig; Goody, R. S. Kinetic Analysis of Four HIV-1 Reverse Transcriptase Enzymes Mutated in the Primer Grip Region of p66: Implications for DNA Synthesis and Dimerization. J. Biol. Chem. 1997, 272, 17581-17587.
28. Pelemans, H.; Esnouf, R.; De Clercq, E.; Balzarini, J. Mutational Analysis of Trp-229 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase (RT) Identifies This Amino Acid Residue as a Prime Target for the Rational Design of New Non-Nucleoside RT Inhibitors. Mol. Pharmol. 2000, 57, 954-960.
29. Hopkins, A. L.; Ren, J.; Tanaka, H.; Baba, B.; Okamato, M.; Stuart, D. L; Stammers, D. K. Design of MKC-442 (Emivirine) Analogues with Improved Activity Against Drug Resistant HIV Mutants. J. Med. Chem. 1999, 42, 4500-4505.
30. Hsiou, Y.; Das, K.; Ding, J.; Clark, A. D., Jr.; Kleim, J.-P.; Rösner, M.; Winkler, L.; Riess, G.; Hughes, S. H.; Arnold, E. Structures of Tyr188Leu Mutant and Wild-type HIV-1 Reverse Transcriptase Complexed with the Non-nucleoside Inhibitor HBY 097: Inhibitor Flexibility is a Useful Design Feature for Reducing Drug Resistance. J. Mol. Biol. 1998, 284, 313-323.
31. Wang, D. P.; Rizzo, R. C.; Tirado-Rives, J.; Jorgensen, W. L. Antiviral drug design: Computational analyses of the effects of the L100I mutation for HIV-RT on the binding of NNRTIs. Bioorg. Med. Chem. Lett. 2001, 11, 2799-2802.
32. Hsiou, Y.; Ding, J.; Das, K.; Clark, A. D., Jr.; Boyer, P. L.; Lewi, P.; Janssen, P. A. J.; Kleim, J. P.; Rosner, M.; Hughes, S. H.; Arnold, E. The Lysl03Asn Mutation of HIV-1 RT: A Novel Mechanism of Drug Resistance. J. Mol. Biol. 2001, 309, 437-445.
33. Das, K.; Clark, A. D., Jr.; Lewi, P. J.; Heeres, J.; De Jonge, M. R.; Koymans, L. M. H.; Vinkers, H. M.; Daeyaert, F.; Ludovici, D. W.; Kukla, M. J.; Corte, B. D.; Kavash, R. W.; Ho, C. Y.; Ye, H.; Lichtenstein, M. A.; Andries, K.; Pauwels, R.; De Béthune, M.-P.; Boyer, P. L.; Clark, P.; Hughes, S. H.; Janssen, P. A. J.; Arnold, E. Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem. 2004, 47, 2550-2560.
34. Udier-Blagovic, M.; Watkins, E. K.; Tirado-Rives, J.; Jorgensen, W. L. Activity Predictions for Efavirenz Analogues with the K103N Mutant of HIV Reverse Transcriptase. Bioorg. Med. Chem. Lett. 2003, 13, 3337-3340.
35. Nanni, R. G.; Ding, J.; Jacobo-Molina, A.; Hughes, S. H.; Arnold, E. Review of HIV-1 Reverse Transcriptase Three-Dimensional Structure: Implications for Drug Design. Perspect. Drug Discovery Des. 1993, 1, 129-150.
36. Yadav, P. N. S.; Das, K.; Ding, J.; Arnold, E.; Yadav, J. S.; Modak, M. J. Structure-based design of inhibitors of HIV-1 reverse transcriptase: A potential Class of bidentate Nonnucleoside Inhibitors. THEOCHEM 1998, 423, 101-112.
37. Ludovici, D. W.; De Corte, B. L.; Kukla, M. J.; Ye, H.; Ho, C. Y.; Lichtenstein, M. A.; Kavash, R. W.; Andries, K.; De Béthune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P. J.; Heeres, J.; Koymans, L. M.; De Jonge, M. R.; Van Aken, K. J.; Daeyaert, F. F.; Das, K.; Arnold, E.; Janssen, P. A. J. Evolution of anti-HIV Drug Candidates. Part 3: Diarylpyrimidine (DAPY) Analogues. Bioorg. Med. Chem. Lett. 2001, 11, 2235-2239.
38. Janssen, P. A. J.; Lewi, P. J.; Arnold, E.; Daeyaert, F.; De Jonge, M.; Heeres, J.; Koymans, L.; Vinkers, M.; Guillemont, J.; Pasquier, E.; Kukla, M.; Ludovici, D.; Andries, K.; De Béthune, M.-P.; Pauwels, R.; Das, K.; Clark, A. D., Jr.; Frenkel, Y. V.; Hughes, S. H.; Medaer, B.; De Knaep, F.; Bohets, H.; De Clerck, F.; Lampo, A.; Williams, P.; Stoffels, P. In search of a novel anti-HIV drug: Multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-cyanoetenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile (R278474-rilpivirine). J. Med. Chem. 2005, 48, 1901-1909.
39. Guillemont, J.; Pasquier, E.; Palandjian, P.; Vernier, D.; Gaurrand, S.; Lewi, P. J.; Heeres, J.; De Jonge, M. R.; Koymans, L. M. H.; Daeyaert, F. F. D.; Vinkers, M. H.; Arnold, E.; Das, K.; Pauwels, R.; Andries, K.; De Béthune, M.-P.; Bettens, E.; Hertogs, K.; Wigerinck, P.; Timmerman, P.; Janssen, P. A. J. Synthesis of Novel Diarylpyrimidine Analogues and Their Antiviral Activity against Human Immunodeficiency Virus Type 1. J. Med. Chem. 2005, 48, 2072-2079.
40. Esnouf, R. M.; Ren, J.; Hopkins, A. L.; Ross, C. K.; Jones, E. Y.; Stammers, D. K.; Stuart, D. I. Unique Features in the Structure of the Complex Between HIV-I Reverse Transcriptase and the bis(heteroaryl)piperazine (BHAP) U-90152 Explain Resistance Mutations for this Non-nucleoside Inhibitor. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 3984-3984.
41. Ren, J.; Nichols, C. E.; Chamberlain, P. P.; Weaver, K. L.; Short, S. A.; Stammers, D. K. Crystal Structures of HIV-1 Reverse Transcriptases Mutated at Codons 100, 106, and 108 and Mechanisms of Resistance to Non-nucleoside Inhibitors. J. Mol Biol. 2004, 336, 569-578.
42. Dueweke, T. J.; Pushkarskaya, T.; Poppe, S. M.; Swaney, S. M.; Zhao, J. Q.; Chen, I. S.; Stevenson, M.; Tarpley, W. G. A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type 1 that confers increased sensitivity to other nonnucleoside inhibitors. Proc. Nat. Acad. Sci. U.S.A. 1993, 90, 4713-4717.
43. Ghosh, M.; Meerts, I. A.; Cook, A.; Bergman, A.; Brouwer, A.; Johnson, L. N. Structure of human transthyretin complexed with bromophenols: Anew mode of binding. Acta Crystallogr. D Biol. Crystallogr. 2000, 56, 1085-1095.
44. Wojtczak, A.; Cody, V.; Luft, J. R.; Pangborn, W. Structures of human transthyretin complexed with thyroxine at 2.0 A resolution and 3',5'-dinitro-N-acetyl-L-thyronine at 2.2 A resolution. Acte Crystallogr. D Biol. Crystallogr. 1996, 52, 758-765.
45. Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Halogen bonds in biological molecules. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 16789-16794.
46. Clark, A. D., Jr.; Jacobo-Molina, A.; Clark, P.; Hughes, S. H.; Arnold, E. Crystallization of Human Immunodeficiency Virus Type 1 Reverse Transcriptase With and Without Nucleic Acid Substrates, Inhibitors and an Antibody Fab Fragment. Methods Enzymol. 1995, 262, 171-185.
47. Otwinowski, Z.; Minor, W., DENZO and SCALEPACK. In Crystallography of Biological Macromolecules; Rossmann, M. G., Arnold, E., Eds.; Kluwer Academic Publishers: Boston, 2001; Vol. F, pp 226-235.
48. Navaza, J. AMoRe: An Automated Package for Molecular Replacement. Acta Crystallogr. A 1994, 50, 157-163.
49. Jones, T. A.; Zou, J.-Y.; Cowan, S. W.; Kjeldgaard, M. Improved Experimental Procedures for Building Protein Models in Electron-Density Maps and the Location of Errors in These Models. Acta Crystallogr. A 1991, 47, 110-119.
50. Briinger, A. T.; Adams, P. D.; Clore, G. M.; De Lano, W. L.; Gros, P.; Grosse-Kunstleve, R. W.; Jiang, J. S.; Kuszewski, J.; Nilges, M.; Pannu, N. S.; Read, R. J.; Rice, L. M.; Simonson, T.; Warren, G. L. Crystallography and NMR System: A New Software Suite for Macromolecular Structure Determination. Acta Crystallogr. D. Biol. Crystallogr. 1998, 54, 905-921.
51. Maestro Molecular Modeling Interface, 6.5; Schrödinger, L.L.C.: New York, 2004.
52. Ding, J.; Das, K; Tantillo, C.; Zhang, W.; Clark, A. D., Jr.; Jessen, S.; Lu, X.; Hsiou, Y.; Jacobo-Molina, A.; Andries, K.; Pauwels, R.; Moereels, H.; Koymans, L.; Janssen, P. A. J.; Smith, R. H., Jr.; Koepke, M. K.; Michejda, C. J.; Hughes, S. H.; Arnold, E. Structure of HIV-1 Reverse Transcriptase in a Complex with the Non-nucleoside Inhibitor α-APA R95845 at 2.8 Å Resolution. Structure 1995, 3, 365-379.
53. Nicholls, A.; Sharp, K. A.; Honig, B. Protein Folding and Association: Insights from the Interfacial and Thermodynamic Properties of Hydrocarbons. Proteins 1991, 11, 281-296.
54. Kraulis, P. J. MolScript: A Program to Produce Both Detailed and Schematic Plots of Protein Structures. Journal Appl. Crystallogr. 1991, 24, 946-950.
55. Kraulis, P. J. MolScript, 2.2.2; Avatar Software AB: Stockholm, Sweden, 1998.
56. Young, C.; Amundsen, C.; Anger, S.; Antler, R.; Baily, J.; Barish, E.; Bayer, D.; Bennett, K.; Bennett, S.; Bowermaster, J.; Buck, D.; Cason, C.; Collins, A.; Dailey, C.; Demlow, S.; Dilger, A.; Littel, J. V. D.; Enzmann, A.; Farmer, D.; Fusner, C.; Harr, D.; Kanakis, T.; Kivisalo, K. J.; Knight, A.; Kretzschmar, L.; Marslett, C.; Massimino, P.; McElhiney, J.; Mickelsen, R. A.; Miller, M., et al. POV-Ray, 3.6; Persistence Of Vision Raytracer Pty. Ltd.: Indianapolis, IN 46224, 2004.