Synthesis and antiviral activity of ethidium-arginine conjugates directed against the TAR RNA of HIV-1

Journal of Medicinal Chemistry

Volumn 42, Issue 20, 1999, Pages 4042-4053

  Peytou, Valérie ^a   Condom, Roger ^a   Patino, Nadia ^a   Guedj, Roger ^a   Aubertin, Anne Marie ^b   Gelus, Nathalie ^b   Bailly, Christian ^b   Terreux, Raphaël ^a   Cabrol Bass, Daniel ^a  

^a UNIVERSITÉ CÔTE D'AZUR   (France)

^b INSERM   (France)

Author keywords

[No Author keywords available]

Indexed keywords

9 [3 [[(ARGININYL BETA ALANYL)AMINOCAPROYL] KETO]PHENYL] 2,7 DIAMINO 10 METHYLPHENANTHRIDINE CHLORIDE; ANTIVIRUS AGENT; ETHIDIUM ARGININE CONJUGATE; UNCLASSIFIED DRUG; VIRUS RNA;

ANTIVIRAL ACTIVITY; ARTICLE; BINDING SITE; CONFORMATIONAL TRANSITION; DRUG CONJUGATION; DRUG STRUCTURE; DRUG SYNTHESIS; GENE EXPRESSION REGULATION; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS 1; MELTING POINT; MOLECULAR MODEL; VIRUS REPLICATION;

ANTI-HIV AGENTS; ARGININE; CELL LINE; ETHIDIUM; HIV-1; HUMANS; MODELS, MOLECULAR; NUCLEIC ACID DENATURATION; RESPONSE ELEMENTS; RIBONUCLEASES; RNA, VIRAL; STRUCTURE-ACTIVITY RELATIONSHIP; TRANS-ACTIVATION (GENETICS); VIRUS REPLICATION;

EID: 0033533791     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm980728e     Document Type: Article

References (63)

1. Barré-Sinoussi, F.; Chermann, J. C.; Rey, F.; Nugeyre, M.; Chamaret, S.; Gruest, J.; Dauguet, C.; Axler-Blin, C.; Vezinet-Brun, F.; Rouzioux, C.; Rozenbaum, W.; Montagnier, L. Isolation of a T-lymphotropic retrovirus from a patient at risk of acquired immune deficiency syndrome (AIDS). Science 1983, 868-870.
2. Kingsman, S. M.; Kingsman, A. J. The regulation of human immunodeficiency virus type-1 gene expression. Eur. J. Biochem. 1996, 491-507.
3. Caputo, A.; Grossi, M. P.; Rossi, C.; Campioni, D.; Balboni, P. G.; Corallini, A.; Barbanti-Brodano, G. The tat gene and protein of the human immunodeficiency virus type 1. Microbiologica 1995, 87-110.
4. Felber, B. K.; Pavlakis, G. N. Molecular biology of HIV-1-positive and negative regulatory elements important for virus expression. AIDS 1993, S51-S62.
5. Marciniak, R. A.; Sharp, P. A. HIV-1 Tat protein promotes formation of non processive elongation complexes. EMBO J. 1991, 4189-4196.
6. Bayer, P.; Kraft, M.; Ejchart, A.; Westendorp, M.; Frank, R.; Rosch, P. Structural studies of HIV-1 Tat protein. J. Mol. Biol. 1995, 529-535.
7. Vives, E.; Charneau, P.; Van Rietschoten, J.; Rochat, H.; Bahraoui, E. Effects of the Tat basic domain on human immunodeficiency virus type 1 trans-activation, using chemically synthesized Tat protein and Tat peptides. J. Virol. 1994, 3343-3353.
8. Karn, J.; Graeble, M. A. New insights into the mechanism of HIV-1 trans-activation. Trends Genet. 1992, 365-368.
9. Tao, J.; Frankel, A. D. Electrostatic interactions modulate the RNA-binding and trans-activation specificities of the HIV and SIV Tat proteins. Proc. Natl. Acad. Sci. U.S.A. 1993, 1571-1575.
10. Churcher, M. J.; Lamont, C.; Hamy, F.; Dingwall, C.; Green, S. M.; Lowe, A. D.; Butler, P. J. G.; Gait, M. J.; Karn, J. High affinity binding of TAR RNA by the human immunodeficiency virus Type-1 Tat protein requires base-pairs in the RNA stem and amino acid residues flanking the basic region. J. Mol. Biol. 1993, 90-110.
11. Weeks, K.; Crothers, D. M. RNA recognition by Tat-derived peptides: interaction in the major groove. Cell 1991, 577-588.
12. Jones, K. A.; Peterlin, B. M. Control of RNA initiation and elongation at the HIV-1 promoter. Annu. Rev. Biochem. 1994, 717-743.
13. Cullen, B. R. Mechanism of action of regulatory proteins encoded by complex retroviruses. Microbiol. Rev. 1993, 375-394.
14. Muesing, M. A.; Smith, D. H.; Capon, D. J. Regulation of mRNA accumulation by HIV trans-activation protein. Cell 1987, 691-704.
15. Aboul-Ela, G.; Karn, J.; Varani, G. Structure of HIV-1 TAR RNA in the absence of ligands reveals a novel conformation of the trinucleotide bulge. Nucleic Acids Res. 1996, 4598-4598.
16. Wang, Z. Y.; Rana, T. M. RNA conformation in the Tat-TAR complex determined by site-specific photocross-linking. Biochemistry 1996, 35, 6491-6499.
17. Aboul-Ela, F.; Karn, J.; Varani, G. The structure of the human immunodeficiency virus type-1 TAR RNA reveals principles of RNA recognition by Tat protein. J. Mol. Biol. 1995, 253, 313-332.
18. Sumner-Smith, M.; Roy, S.; Barnett, R.; Reid, L. S.; Kuperman, R.; Delling, U.; Sonenberg, N. Critical chemical features in trans-acting-responsive RNA are required for interaction of HIV-1 Tat protein. J. Virol. 1991, 5196-5202.
19. Pritchard, C. E.; Grasby, J. A.; Hamy, F.; Zacharek, A. M.; Singh, M.; Karn, J.; Gait, M. J. Methylphosphonate mapping of phosphate contacts critical for RNA recognition by the human immunodeficiency virus tat and rev proteins. Nucleic Acids Res. 1994, 2592-2600.
20. Hamy, F.; Asseline, U.; Grasby, J.; Iwai, S.; Pritchard, C.; Slim, G.; Butler, P. J. G.; Karn, J.; Gait, M. J. Hydrogen-bonding contacts in the major groove are required for human immunodeficiency virus type-1 Tat protein recognition of TAR RNA. J. Mol. Biol. 1993, 111-123.
21. Calnan, B. J.; Tidor, B.; Biancalana, S.; Hudson, D.; Frankel, A. D. Arginine-mediated RNA recognition: the arginine fork. Science 1991, 1167-1171.
22. Delling, U.; Roy, S.; Sumner-Smith, M.; Barnett, R.; Reid, L.; Rosen, C. A.; Sonenberg, N. The number of positively charged amino acids in the basic domain of Tat is critical for trans-activation and complex formation with TAR RNA. Proc. Natl. Acad. Sci. U.S.A. 1991, 6234-6238.
23. Tao, J.; Chen, L.; Frankel, A. D. Dissection of the proposed base triple in HIV TAR RNA indicates the importance of the Hoogsteen interaction. Biochemistry 1997, 3491-3495.
24. Puglisi, J. D.; Tan, R.; Calnan, B. J.; Frankel, A. D.; Williamson, J. R. Conformation of the TAR-arginine complex by NMR. Science 1992, 76-80.
25. Puglisi, J. D.; Chen, L.; Frankel, A. D.; Williamson, J. R. Role of RNA structure in arginine recognition of TAR RNA. Proc. Natl. Acad. Sci. U.S.A. 1993, 3680-3684.
26. Tao, J.; Frankel, A. D. Specific binding of arginine to TAR RNA. Proc. Natl. Acad. Sci. U.S.A. 1992, 2723-2726.
27. Wilson, W. D.; Ratmeyer, L.; Zhao, M.; Strekowski, L.; Boykin, D. The search for structure-specific nucleic acid-interactive drugs: effects of compound structure on RNA versus DNA interaction strength. Biochemistry 1993, 32, 4098-4104.
28. Jain, S. C.; Sobell, H. M. Visualization of drug-nucleic acid interactions at atomic resolution. VIII. Structures of two ethidium/ dinucleoside monophosphate crystalline complexes containing ethidium: cytidylyl(3′-5′)guanosine. J. Biomol. Struct. Dyn. 1984, 1179-1194.
29. Kastrup, R. V.; Young, M. A.; Krugh, T. R. Ethidium bromide complexes with self-complementary deoxytetranucleotides. Demonstration and discussion of sequence preferences in the intercalative binding of ethidium bromide. Biochemistry 1978, 17, 485-4865.
30. Krugh, T. R.; Reinhardt, C. G. Evidence for sequence preferences in the intercalative binding of ethidium bromide to dinucleoside monophosphates. J. Mol. Biol. 1975, 133-162.
31. Fox, K. R.; Waring, M. J. Footprinting at low temperature: evidence that ethidium and other simple intercalators can discriminate between different nucleotide sequences. Nucleic Acids Res. 1987, 491-507.
32. White, S. A.; Draper, D. E. Single base bulges in small RNA hairpins enhance binding and promote an allosteric transition. Nucleic Acid Res. 1987, 4049-4064.
33. White, S. A.; Draper, D. E. Effects of single-base bulges on intercalator binding to small RNA and DNA hairpins and a ribosomal RNA fragment. Biochemistry 1989, 28, 1892-1897.
34. Yao, S.; Wilson, W. D. A molecular mechanics investigation of RNA complexes. I. Ethidium intercalation in an HIV-1 TAR RNA sequence with an unpaired adenosine. J. Biomol. Struct. Dyn. 1992, 367-387.
35. Ratmeyer, L. S.; Vinayak, R.; Zon, G.; Wilson, W. D. An ethidium analogue that binds with high specificity to a base-bulged duplex from the TAR RNA region of the HIV-1 genome. J. Med. Chem. 1992, 35, 966-968.
36. Veal, J. M.; Wilson, W. D. Modeling of nucleic acid complexes with cationic ligands: a specialized molecular mechanics force field and its application. J. Biomol. Struct. Dyn. 1991, 1119-1145.
37. Mei, H.-Y.; Cui, M.; Heldsinger, A.; Lemrow, S. M.; Loo, J. A.; Sannes-Lowery, K. A.; Sharmeen, L.; Czarnik, A. W. Inhibitors of protein-RNA complexation that target the RNA: Specific recognition of human immunodeficiency virus type 1 TAR RNA by small organic molecules. Biochemistry 1998, 14204, 14204-14212.
38. Hamy, F.; Felder, E. R.; Heizmann, G.; Lazdins, J.; Aboul-Ela, F.; Varani, G.; Karn, J.; Klimkait, T. An inhibitor of the Tat/ TAR RNA interaction that effectively suppresses HIV-1 replication. Proc. Natl. Acad. Sci. U.S.A. 1997, 3548-3553.
39. Chen, Q.; Shafer, R. H.; Kuntz, I. D. Structure-based discovery of ligands targeted to the RNA double helix. Biochemistry 1997, 11402-11407.
40. Pearson, N. D.; Prescott, C. D. RNA as a drug target. Chem. Biol. 1997, 409-414.
41. Mei, H. Y.; Mack, D. P.; Galan, A. A.; Halim, N. S.; Heldsinger, A.; Loo, J. A.; Moreland D. W.; Sannes-Lowery, K. A.; Sharmeen, L.; Truong, H. N.; Czarnik, A. W. Discovery of selective, small-molecule inhibitors of RNA complexes - I. The Tat protein/TAR RNA complexes required for HIV-1 transcription. Bioorg. Med. Chem. 1997, 1173-1184.
42. Kurz, K.; Gobel, M. W. Hydrolytical cleavage of TAR RNA, the trans-activation responsive region of HIV-1, by a bis(guanidinium) catalyst attached to arginine. Helv. Chim. Acta 1996, 1967-1979.
43. Wilson, W. D.; Tanious, F. A.; Fernandez-Saiz, M.; Rigl, C. T. Evaluation of drug-nucleic acid interactions by thermal melting curves. Methods Mol. Biol. 1997, 219-240.
44. Lapidot, A.; Ben-Asher, E.; Eisenstein, M. Tetrahydropyrimidine derivatives inhibit binding of a Tat-like, arginine-containing peptide, to HIV TAR RNA in vitro. FEBS Lett. 1995, 33-38.
45. Michne, W. F.; Schroeder, J. D.; Bailey, T. R.; Neumann, H. C.; Cooke, D.; Young, D. C.; Hughes, J. V.; Kingsley, S. D.; Ryan, K. A.; Putz, H. S. Keto/enol epoxy steroids as HIV-1 Tat inhibitors: structure-activity relationships and pharmacophore localization. J. Med. Chem. 1995, 38, 3197-3206.
46. Mei, H. Y.; Galan, A. A.; Halim, N. S.; Mack, D. P.; Moreland, D. W.; Sanders, K. B.; Truong, H. N.; Czarnik, A. W. Inhibition of an HIV-1 Tat-derived peptide binding to TAR RNA by aminoglycoside antibiotics. Bioorg. Med. Chem. Lett. 1995, 2755-2760.
47. 2. Antiviral Chem. Chemother. 1994, 128-129.
48. Wilson, W. D.; Ratmeyer, L.; Cegla, M. T.; Spychala, J.; Voykin, D.; Demeunynck, M.; Lhomme, J.; Krishnan, G.; Kennedy, D.; Vinayak, R.; Zon, G. Bulged-base nucleic acids as potential targets for antiviral drug action. New J. Chem. 1994, 419-423.
49. Sinet, M.; Kubar, J.; Condom, R.; Patino, N.; Guedj, R. The protein Tat of HIV - Potential target in antiretroviral chemotherapy. Médecine / Sciences 1993, 1342-1351.
50. Kuhlmann, K. F.; Charbeneau, N. J.; Mosher, C. W. Synthesis, DNA-binding and biological activity of a double intercalating analogue of ethidium bromide. Nucleic Acids Res. 1978, 2629-2641.
51. 32P-end-labeled DNA. Biochemistry 1988, 8606-8613.
52. Lion, C.; Boukou-Poba, J. P.; Charvy, C. Synthèse dans la chimie des phénanthridines. I. Recherches des conditions optimales dans la préparation d'alkyl-6 phénanthridines et de leur sel. Bull. Soc. Chim. Belg. 1989, 557-573.
53. Lion, C.; Boukou-Poba, J. P.; Charvy, C. Synthèse dans la chimie des phénanthridines. III. Préparation de quelques modèles d'acides ω-(diamino-3,8-phénanthridinyl-6) carboxyliques. Bull. Soc. Chim. Belg. 1990, 171-181.
54. Fodor, G.; Nagubandi, S. Correlation of the Von Braun, Ritter, Bischler-Napieralski, Beckmann and Schmidt reactions via nitrilium salt intermediates. Tetrahedron 1980, 1279-1300.
55. G-2,2,5,7,8-Pentamethylchroman-6-sulphonyl-L-arginine: a new acid labile derivative for peptide synthesis. Tetrahedron Lett. 1987, 2287-2290.
56. G-2,2,5,7,8-pentamethylchroman-6-sulphonyl-L-arginine. Tetrahedron Lett. 1991, 6353-6370.
57. Terreux, R.; Peytou, V.; Condom, R.; Cabrol-Bass, D.; Guedj, R. Modeling of interaction between new ethidium derivatives and TAR RNA of HIV-1. J Chem. Inf. Comput. Sci. 1999, 413-419.
58. It is very unlikely that the drug binds directly to the RNase enzymes for two reasons. First, we used the same concentration of enzyme to cleave the RNA alone and the RNA complexed with the drug. If the ligand was bound to the enzyme, then the level of RNA cleavage would be reduced, but this is not the case. Second, we investigated the binding of the drug to another hairpin RNA related to RRE RNE from HIV-1, but no cleavage protection was detected. For these reasons, we are convinced that the observed effects reflect the interaction of the drug with the RNA and not with the enzyme.
59. Moog, C.; Wick, A.; Leber, P.; Kirn, A.; Aubertin, A. M. Bicyclic imidazo derivatives, a new class of highly selective inhibitors for the HIV-1. Antiviral Res. 1994, 275-288.
60. 50, synergism, antagonism, low-dose risk, receptor binding and enzyme kinetics. Computer software for Apple II series and IBM-PC and instruction manual; Elsevier-Biosoft, Elsevier Science: Cambridge, U.K., 1985.
61. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Imunnol. Methods 1983, 55-63.
62. Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols, D.; Herdewijn, P.; Desmyter, J.; De Clercq, E. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods 1988, 309-321.
63. Génu-Dellac, C.; Gosselin, G.; Puech, F.; Henry, J. C.; Aubertin, A. M.; Aubert, G.; Kirn, A.; Imbach, J. L. Systematic synthesis and antiviral evaluation of α-L-arabinofuranosyl and 2′-deoxy-α-L-erythro-pentufuranosyl nucleosides of the five naturally occurring nucleic acid bases. Nucleosides Nucleotides 1991, 1345-1376.