Structure-based Drug Design Targeting an Inactive RNA Conformation: Exploiting the Flexibility of HIV-1 TAR RNA

Journal of Molecular Biology

Volumn 336, Issue 3, 2004, Pages 625-638

  Murchie, Alastair I H ^a   Davis, Ben ^a   Isel, Catherine ^b   Afshar, Mohammad ^a,c   Drysdale, Martin J ^a   Bower, Justin ^a   Potter, Andrew J ^a   Starkey, Ian D ^a   Swarbrick, Terry M ^a   Mirza, Shabana ^a,d   Prescott, Catherine D ^a,e   Vaglio, Philippe ^a   Aboul ela, Fareed ^a   Karn, Jonathan ^b,f  

^a RiboTargets Ltd   (United Kingdom)

^b MRC LABORATORY OF MOLECULAR BIOLOGY   (United Kingdom)

^c Ariana Pharma   (France)

^d UNIVERSITY OF SHEFFIELD   (United Kingdom)

^e Avlar BioVentures Limited   (United Kingdom)

^f CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Anti virals; FRET; HIV; Ligand RNA interactions; Tat TAR interaction

Indexed keywords

GUANIDINE; LIGAND; RBT 158; RBT 162; RBT 171; RBT 203; RBT 392; RBT 415; RBT 417; RBT 418; RBT 428; RBT 528; RBT 550; TRANSACTIVATOR PROTEIN; TRANSCRIPTION FACTOR AP 1; UNCLASSIFIED DRUG; VIRUS RNA;

ARTICLE; ASSAY; CELL FREE SYSTEM; CONTROLLED STUDY; DRUG DESIGN; FLUORESCENCE RESONANCE ENERGY TRANSFER; HUMAN IMMUNODEFICIENCY VIRUS 1; IN VITRO STUDY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE; PRIORITY JOURNAL; RNA BINDING; RNA CONFORMATION;

HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS 1;

EID: 10744222241     PISSN: 00222836     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.jmb.2003.12.028     Document Type: Article

References (56)

1. Gallego J., Varani G. Targeting RNA with small-molecule drugs: therapeutic promise and chemical challenges. Acc. Chem. Res. 34:2001;836-843.
2. Drysdale M.J., Lentzen G., Matassova N., Murchie A.I.H., Aboul-ela F., Afshar M. RNA as a drug target. Prog. Med. Chem. 39:2002;73-119.
3. Foreyen M., Herdewijn P. RNA as a target for drug design, the example of Tat-TAR interaction. Curr. Top. Med. Chem. 2:2002;1123-1145.
4. Karn J. Tackling Tat. J. Mol. Biol. 293:1999;235-254.
5. Delling U., Reid L.S., Barnett R.W., Ma M.Y.-X., Climie S., Sumner-Smith M., Sonenberg N. Conserved nucleotides in the TAR RNA stem of human immunodeficiency virus type 1 are critical for Tat binding and trans activation: model for TAR RNA tertiary structure. J. Virol. 66:1992;3018-3025.
6. Dingwall C., Ernberg I., Gait M.J., Green S.M., Heaphy S., Karn J., et al. Human immunodeficiency virus 1 tat protein binds trans-activation- responsive region (TAR) RNA in vitro. Proc. Natl Acad. Sci. USA. 86:1989;6925-6929.
7. Churcher M.J., Lamont C., Hamy F., Dingwall C., Green S.M., Lowe A.D., et al. 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. 230:1993;90-110.
8. Colvin R.A., Garcia-Blanco M.A. Unusual structure of the human immunodeficiency virus type 1 trans-activation response element. J. Virol. 66:1992;930-935.
9. Weeks K.M., Ampe C., Schultz S.C., Steitz T.A., Crothers D.M. Fragments of the HIV-I Tat protein specifically bind TAR RNA. Science. 249:1990;1281-1285.
10. Weeks K.M., Crothers D.M. RNA recognition by Tat-derived peptides: interaction in the major groove? Cell. 66:1991;577-588.
11. Hamy F., Asseline V., Grasby J., Iwai S., Pritchard C., Slim G., et al. Hydrogen bonding contacts in the major groove are required for human immunodeficiency virus type-1 Tat protein recognition of TAR RNA. J. Mol. Biol. 230:1993;111-123.
12. 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. Nucl. Acids Res. 22:1994;2592-2600.
13. Arzumanov A., Walsh A.P., Rajwanshi V.K., Kumar R., Wengel J., Gait M.J. Inhibition of HIV-1 tat-dependent trans activation by steric block chimeric 2′-O-methyl/LNA oligoribonucleotides. Biochemistry. 40:2001;14645-14654.
14. Holmes S.C., Arzumanov A.A., Gait M.J. Steric inhibition of human immunodeficiency virus type-1 Tat-dependent trans-activation in vitro and in cells by oligonucleotides containing 2′-O-methyl G-clamp ribonucleoside analogues. Nucl. Acids Res. 31:2003;2759-2768.
15. Mischiati C., Jeang K.-T., Feriotto G., Breda L., Borgatti M., Bianchi N., Gambari R. Aromatic polyamidines inhibiting the tat-induced HIV-1 transcription recognize structured TAR-RNA. Antisense Nucl. Acid Drug Dev. 11:2001;209-217.
16. Kaushik N., Basu A., Palumbo P., Myers R.L., Pandey V.N. Anti-TAR polyamide nucleotide analog conjugated with a membrane-permeating peptide inhibits human immunodeficiency virus type 1 production. J. Virol. 76:2002;3881-3891.
17. Puglisi J.D., Tan R., Calnan B.J., Frankel A.D., Williamson J.R. Conformation of the TAR RNA-arginine complex by NMR spectroscopy. Science. 257:1992;76-80.
18. Aboul-ela F., Karn J., Varani G. The structure of the human immunodeficiency virus type-1 TAR reveals principles of RNA recognition by Tat protein. J. Mol. Biol. 253:1995;313-332.
19. Aboul-ela F., Karn J., Varani G. Structure of HIV-1 TAR RNA in the absence of ligands reveals a novel conformation of the trinucleotide bulge. Nucl. Acids Res. 24:1996;3974-3981.
20. Brodsky A.S., Williamson J.R. Solution structure of the HIV-2 TAR-argininamide complex. J. Mol. Biol. 267:1997;624-639.
21. *C mutant-argininamide complex. Nucl. Acids Res. 26:1998;1991-1995.
22. Ippolito J., Steitz T.A. A 1.3 Å resolution crystal structure of the HIV-1 trans-activation response region RNA stem reveals a metal ion-dependent bulge conformation. Proc. Natl Acad. Sci. USA. 95:1998;9819-9824.
23. Long K.S., Crothers D.M. Characterization of the solution conformations of unbound and Tat peptide-bound forms of HIV-1 TAR RNA. Biochemistry. 38:1999;10059-10069.
24. Al-Hashimi H.M., Gosser Y., Gorin A., Hu W., Majumdar A., Patel D.J. Concerted motions in HIV-1 TAR RNA may allow access to bound state conformations: RNA dynamics from NMR residual dipolar couplings. J. Mol. Biol. 315:2002;95-102.
25. Davis, B., Afshar, M., Varani, G., Murchie, A. I. H., Karn, J., Lentzen, G., Drysdale, M., Bower, J., Potter, A. J., Starkey, I. D., Swarbrick, T. & Aboul-ela, F. (2004). Moulding RNA conformation by stabilisation of electrostatic "hot spots" how ligand-induced conformational change in rna mediates specific interactions. J. Mol. Biol. In the press.
26. Hamy F., Felder E.R., Heizmann G., Lazdins J., Aboul-ela F., Varani G., et al. An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication. Proc. Natl Acad. Sci. USA. 94:1997;3548-3553.
27. Faber C.S., Schweimer H., Rosch K.P. Structural rearrangements of HIV-Tat-responsive RNA upon binding of neomycin B. J. Biol. Chem. 275:2000;20660-20666.
28. Hwang S., Tamilarasu N., Ryan K., Huq I., Richter S., Still W.C., Rana T.M. Inhibition of gene expression in human cells through small molecule-RNA interactions. Proc. Natl Acad. Sci. USA. 96:1999;12997-13002.
29. Du Z., Lind K.E., James T.L. Structure of TAR RNA complexed with a Tat-TAR interaction nanomolar inhibitor that was identified by computational screening. Chem. Biol. 9:2002;707-712.
30. Isel C., Karn J. Direct evidence that HIV-1 tat stimulates RNA polymerase II carboxyl-terminal domain hyperphosphorylation during transcriptional elongation. J. Mol. Biol. 290:1999;929-941.
31. Keen N.J., Gait M.J., Karn J. Human immunodeficiency virus type-1 Tat is an integral component of the activated transcription-elongation complex. Proc. Natl Acad. Sci. USA. 93:1996;2505-2510.
32. Keen N.J., Churcher M.J., Karn J. Transfer of Tat and release of TAR RNA during the activation of the human immunodeficiency virus type-1 transcription elongation complex. EMBO J. 16:1997;5260-5272.
33. West M.J., Karn J. Stimulation of Tat-associated kinase-independent transcriptional elongation from the human immunodeficiency virus type-1 long terminal repeat by a cellular enhancer. EMBO J. 18:1999;1378-1386.
34. Kim Y.K., Bourgeois C.F., Isel C., Churcher M.J., Karn J. Phosphorylation of the RNA polymerase II carboxyl-terminal domain by CDK9 is directly responsible for human immunodeficiency virus type 1 Tat-activated transcriptional elongation. Mol. Cell. Biol. 22:2002;4622-4637.
35. Jones C.R., Bolton P.H., Kearns D.R. Ethidium bromide binding to transfer RNA: transfer RNA as a model system for studying drug-RNA interactions. Biochemistry. 17:1978;601-607.
36. Cho J., Rando R.R. Specific binding of hoechst 33258 to site 1 thymidylate synthase mRNA. Nucl. Acids Res. 28:2000;2158-2163.
37. Ratmeyer L., Zapp M.L., Green M.R., Vinayak R., Kumar A., Boykin D.W., Wilson W.D. Inhibition of HIV-1 Rev-RRE interaction by diphenylfuran derivatives. Biochemistry. 35:1996;13689-13696.
38. Dassonneville L., Hamy F., Colson P., Houssier C., Bailly C. Binding of Hoeschst 33258 to the TAR RNA of HIV-1. Recognition of a pyrimidine bulge-dependent structure. Nucl. Acids Res. 25:1997;4487-4492.
39. Li K., Davis T.M., Bailly C., Kumar A., Boykin D.W., Wilson W.D. A heterocyclic inhibitor of the rev-RRE complex binds to RRE as a dimer. Biochemistry. 40:2001;1150-1158.
40. Nelson J.W., Tinoco I. Jr. Ethidium ion binds more strongly to a DNA double helix with a bulged cytosine than to a regular double helix. Biochemistry. 24:1985;6416-6421.
41. Hamy F., Brondani V., Florsheimer A., Stark W., Blommers M.J.J., Klimkait T. A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition. Biochemistry. 37:1998;5086-5095.
42. Mei H.-Y., Cui M., Heldsinger A., Lemrow S.M., Loo J.A., Sannes-Lowery K.A., et al. Inhibitors of protein-RNA complexation that target the RNA: specific recognition of human immunodeficiency virus type 1 TAR RNA by small organic molecules. Biochemistry. 37:1998;14204-14212.
43. Wang S., Huber P.W., Cui M., Czarnik A.W., Mei H.-Y. Binding of neomycin to the TAR element of HIV-1 RNA induces dissociation of Tat protein by an allosteric mechanism. Biochemistry. 37:1998;5549-5557.
44. Gelus N., Bailly C., Hamy F., Klimkait T., Wilson W.D., Boykin D.W. Inhibition of HIV-1 Tat-TAR interaction by diphenylfuran derivatives: effects of the terminal basic side chains. Bioorg. Med. Chem. 7:1999;1089-1096.
45. Lind K.E., Du Z., Fujinaga K., Peterlin B.M., James T.L. Structure-based computational database screening, in vitro assay, and NMR assessment of compounds that target RNA. Chem. Biol. 9:2002;185-193.
46. Mei H.-Y., Cui M., Heldsinger A., Lemrow S.M., Loo J.A., Sannes-Lowery K.A., et al. Inhibitors of protein-RNA complexation that target the RNA: specific recognition of human immunodeficiency virus type 1 TAR RNA by small organic molecules. Biochemistry. 37:1998;14204-14212.
47. Schindler T., Bornmann W., Peelicena P., Miller W.T., Clarkson B., Kuriyan J. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 289:2000;1938-1942.
48. Yu L., Oost T.K., Schkeryantz J.M., Yang J., Janowick D., Fesik S.W. Discovery of aminoglycoside mimetics by NMR-based screening of Escherichia coli A-site RNA. J. Am. Chem. Soc. 125:2003;4444-4450.
49. Swayze E.E., Jefferson E.A., Sannes-Lowery K.A., Blyn L.B., Risen L.M., Arakawa S., et al. SAR by MS: a ligand based technique for drug lead discovery against structured RNA targets. J. Med. Chem. 45:2002;3816-3819.
50. Milligan J.F., Uhlenbeck O.C. Synthesis of small RNAs using T7 RNA polymerase. Methods Enzymol. 180:1988;51-62.
51. Varani G., Aboul-ela F., Allain F.H.-T. NMR investigation of RNA structure. Prog. Nucl. Magn. Reson. Spectrosc. 29:1996;51-127.
52. Puglisi J.D., Tinoco I. Absorbance melting curves of RNA. Methods Enzymol. 180:1989;304-325.
53. Delaglio F., Grzesiak S., Vuister G., Zhu G., Pfeifer J., Bax A. NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR. 6:1995;277-293.
54. Diamond R. On the multiple simultaneous superposition of molecular structures by rigid body transformations. Protein Sci. 1:1992;1279-1287.
55. Diamond R. Coordinate-based cluster analysis. Acta Crystallog. sect. D. 51:1995;127-135.
56. Karn J., Gait M.J., Churcher M.J., Mann D.A., Mikaelian I.P.C. Control of human immunodeficiency virus gene expression by the RNA binding proteins Tat and Rev. Nagai K., Mattai I.W. RNA-Protein Interactions. 1994;192-220 IRL Press, Oxford.