NMR-based discovery of lead inhibitors that block DNA binding of the human papillomavirus E2 protein

Journal of Medicinal Chemistry

Volumn 40, Issue 20, 1997, Pages 3144-3150

  Hajduk, Philip J ^a   Dinges, Jürgen ^a   Miknis, Gregory F ^a   Merlock, Megan ^a   Middleton, Tim ^a   Kempf, Dale J ^a   Egan, David A ^a   Walter, Karl A ^a   Robins, Terry S ^a,b   Shuker, Suzy B ^a   Holzman, Thomas F ^a   Fesik, Stephen W ^a  

^a ABBOTT LABORATORIES   (United States)

^b Specialty Laboratories   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 [3' (3'',5'' DICHLOROPHENOXY)PHENYL] 2,4 PENTADIENOIC ACID; ANTIVIRUS AGENT; BIPHENYL DERIVATIVE; UNCLASSIFIED DRUG; VIRUS PROTEIN;

ANTIVIRAL ACTIVITY; ARTICLE; DNA BINDING; DRUG ACTIVITY; DRUG SCREENING; DRUG STRUCTURE; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; STRUCTURE ACTIVITY RELATION; VIRUS INHIBITION; WART VIRUS;

ANTIVIRAL AGENTS; BINDING SITES; BIPHENYL COMPOUNDS; BOVINE PAPILLOMAVIRUS 1; CRYSTALLOGRAPHY, X-RAY; DNA; DNA-BINDING PROTEINS; DRUG DESIGN; HUMANS; LIGANDS; MAGNETIC RESONANCE SPECTROSCOPY; MODELS, CHEMICAL; MODELS, MOLECULAR; PAPILLOMAVIRIDAE; PROTEIN CONFORMATION; REPRESSOR PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP; TRANS-ACTIVATORS; VIRAL PROTEINS;

EID: 9844252882     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9703404     Document Type: Article

References (28)

1. Beckter, T. M.; Stone, K. M.; Alexander, E. R. Genital Human Papillomavirus Infectioni: A Growing Concern. Obstet. Gynecol. Clin. North Am. 1987, 14, 389-396.
2. Pfister, H. Human Papillomaviruses and Skin Cancer. Cancer Biol. 1992, 3, 263-271.
3. Garcia-Carranca, A.; Gariglio, P. V. Molecular Aspects of Human Papillomaviruses and their relation to uterine cervix cancer. Rev. Invest. Clin. (Mexico) 1993, 45, 85-92.
4. Prakash, S. S.; Grossman, S. R.; Pepinsky, R. B.; Laimins, L. A.; Androphy, E. J. Amino Acids Necessary for DNA Contact and Dimerization Imply Novel Motifs in the Papillomavirus E2 Trans-activator. Genes Dev. 1992, 6, 105-116.
5. Haugen, T. H.; Cripe, T. P.; Ginder, G. D.; Karin, M.; Turek, L. P. Trans-activation of an Upstream Early Gene Promoter of Bovine Papilloma Virus-1 by a Product of the Viral E2 Gene. EMBO J. 1987, 6, 145-152.
6. Ustav, M.; Stenlund, A. Transient Replication of BPV-1 Requires Two Viral Polypeptides Encoded by the El and E2 Open Reading Frames. EMBO J. 1991, 10, 449-457.
7. Mohr, I. J.; Clark, R.; Sun, S.; Androphy, E. J.; MacPherson, P.; Botchan, M. R. Targeting the El Replication Protein to the Papillomavirus Origin of Replication by Complex Formation with the E2 Transactivator. Science 1990, 250, 1694-1699.
8. Cowsert, L. M.; Fox, M. C.; Zon, G.; Mirabelli, C. K. In vitro evaluation of phosphorothioate oligonucleotides targeted to the E2-messanger-RNA of Papillomavirus-potential treatment for genital warts. Antimicrob. Agents Chemother. 1993, 37, 171-177.
9. Crooke, S. T.; Mirabelli, C. K.; Ecker, D. J.; Cowsert, L. M. Antisense Oligonucleotide Inhibition of Papillomavirus. PCT International, WO 9320095, Oct 14, 1993, ISIS Pharmaceuticals.
10. Androphy, E. J.; Barsoum, J. G. Inhibitors of the trans-activating function of Papillomavirus E2 proteins, PCT International. WO 9212728, Aug 6, 1992, Biogen Inc.
11. Pepinsky, R. B.; Androphy, E. J.; Corina, K.; Brown, R.; Barsoum, J. Specific Inhibition of a Human Papillomavirus E2 Trans-Activator by Intracelluar Delivery of Its Receptor. DNA Cell Biol. 1994, 13, 1011-1019.
12. Androphy, E. J.; Lowy, D. R.; Schiller, J. T. Inhibition of Papillomavirus Expression with Oligonucleotides or Blocking Proteine. Eur. Pat. Appl., EP 302758, Feb 8, 1989, New England Medical Center Hospitals, Inc.
13. Hegde, R. S.; Grossman, S. R.; Laimins, L. A.; Sigler, P. B. Crystal Structure at 1.7A of the Bovine Papillomavirus-1 E2 DNA-Binding Domain Bound to its DNA Target. Nature 1992, 359, 505-512.
14. Liang, H.; Petros, A. M.; Meadows, R. P.; Yoon, H. S.; Egan, D. A.; Walter, K.; Holzman, T. F.; Robins, T.; Fesik, S. W. Solution Structure of the DNA-Binding Domain of a Human Papillomavirus E2 Protein: Evidence for Flexible DNA-Binding Regions. Biochemistry 1996, 35, 2095-2103.
15. Shuker, S. B.; Hajduk, P. J.; Meadows, R. P.; Fesik, S. W. Discovering High-Affinity Ligands for Proteins: SAR by NMR. Science 1996, 274, 1531-1534.
16. Hajduk, P. J.; Sheppard, G.; Nettesheim, D. G.; Olejniczak, E. T.; Shuker, S. B.; Meadows, R. P.; Steinman, D. H.; Carrera, G. M.; Marcotte, P. A.; Severin, J.; Walter, K.; Sith, H.; Gubbins, E.; Simmer, R.; Holzman, T. F.; Morgan, D. W.; Davidsen, S. K. Discovery of Potent Nonpeptide Inhibitors of Stromelysin Using SAR by NMR. J. Am. Chem. Soc. 1997, 119, 5818-5827.
17. Approximately 2000 compounds were screened against the DNA-binding domain of E2.
18. Kay, L. E.; Keifer, P.; Saarinen, T. Pure Absorption Gradient Enhanced Heteronuclear Single Quantum Correlation Spectroscopy with Improved Sensitivity. J. Am. Chem. Soc. 1992, 114, 10663-10665.
19. Frenette, R.; Friesen, R. W. Biaryl Synthesis via Suzuki Coupling on Solid Support. Tetrahedron Lett. 1994, 35, 9177-9180.
20. Guiles, J. W.; Johnson, S. G.; Murray, W. V. Solid-Phase Suzuki Coupling for C-C Bond Formation. J. Org. Chem. 1996, 61, 5169-5171.
21. Topliss, J. G.; Martin, Y. C. Drug Design; Ariens, E. J., Ed.; Academic Press: New York, 1975; Vol. 5, pp 1-21.
22. Hansch, C.; Unger, S. H.; Forsythe, A. B. Strategy in Drug Design, Cluster Analysis as an Aid in the Selection of Substituents. J. Med. Chem. 1973, 16, 1212-1222.
23. This compound was not in fast exchange on the NMR time scale. Therefore, chemical shifts could not be monitored as a function of ligand concentration and dissociation constants could not be obtained.
24. Matsubara, H.; Steo, K.; Tahara, T.; Takahashi, S. 2,5-Diaryl-1,3,2-dioxaborinanes - A New Series of Liquid Crystals. Bull. Chem. Soc. Jpn. 1989, 62, 3896.
25. Prepared according to Kates, S. A.; Daniels, S. B.; Albericio, F. Automated Allyl Cleavage for Continuous-Flow Synthesis of Cyclic and Branched Peptides. Anal. Biochem. 1993, 212, 303.
26. 13C Spin Pairs. J. Magn. Reson. 1992, 96, 199-204.
27. Brünger, A. T. X-PLOR Version 3.1: A System for X-ray Crystallography and NMR; Yale University Press: New Haven, CT, 1992.
28. Carson, M. Ribbon Models of Macromolecules. J. Mol. Graph. 1987, 5, 103.