RNA as a drug target: Chemical, modelling, and evolutionary tools

Current Opinion in Biotechnology

Volumn 9, Issue 1, 1998, Pages 66-73

  Hermann, Thomas ^a   Westhof, Eric ^a  

^a INST DE BIOL MOLEC ET CELLULAIRE   (France)

Author keywords

[No Author keywords available]

Indexed keywords

AMINOGLYCOSIDE ANTIBIOTIC AGENT; ANTIBIOTIC AGENT; ANTIVIRUS AGENT; BLEOMYCIN; FRAMYCETIN; KANAMYCIN A; LIVIDOMYCIN; PAROMOMYCIN; RIBOSOME RNA; RNA; TOBRAMYCIN; VIOMYCIN; ZINOSTATIN;

COMPLEX FORMATION; DRUG BINDING; DRUG TARGETING; ELECTRICITY; EVOLUTION; HYDROGEN BOND; MOLECULAR MODEL; PRIORITY JOURNAL; REVIEW; RNA BINDING; RNA STRUCTURE;

EID: 0031933080     PISSN: 09581669     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0958-1669(98)80086-4     Document Type: Article

References (86)

1. Ellington AD. Using in vitro nucleic acid selections for conventional drug design. Drug Dev Res. 33:1994;102-115.
2. Ellman J, Stoddard B, Wells J. Combinatorial thinking in chemistry and biology. Proc Natl Acad Sci USA. 94:1997;2779-2782.
3. Park WKC, Auer M, Jaksche H, Wong CH. Rapid combinatorial synthesis of aminoglycoside antibiotic mimetics: use of a polyethylene glycol-linked amine and a neamine-derived aldehyde in multiple component condensation as a strategy for the discovery of new inhibitors of the HIV RNA Rev responsive element. of special interest J Am Chem Soc. 118:1996;10150-10155 In this straightforward study, combinatorial chemistry was used to synthesize a number of aminoglycoside mimetics based on neamine, the central building block conserved among aminoglycoside antibiotics which are active against functional RNAs. The activity of the newly synthesized compounds was tested for their capacity to inhibit the binding of the HIV regulatory Rev protein to its target RNA.
4. Tong G, Nielsen J. A convergent solid-phase synthesis of actinomycin analogues - towards implementation of double-combinatorial chemistry. Bioorg Med Chem. 4:1996;693-698.
5. Hamy F, Felder ER, 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. of special interest Proc Natl Acad Sci USA. 94:1997;3548-3553 This study describes comprehensively the search for a Tat - TAR inhibitor by outlining several stages of the investigation, such as the drug synthesis by combinatorial chemistry, NMR-based molecular modelling studies on the drug - RNA complex and, finally, in vivo inhibition assays. Starting from pools of a partially randomized peptoid/peptide, consecutive rounds of binding selection were used to identify step by step the residues that result in a molecule which binds to TAR RNA and inhibits Tat binding in vitro at nanomolar concentrations.
6. Wilson WD, Ratmeyer L, Zhao M, Ding D, McConnaughie AW, Kumar A, Boykin DW. Design and analysis of RNA structure-specific agents as potential antivirals. J Mol Recogn. 9:1996;187-196.
7. Hecht SM. Strategies for RNA recognition. of special interest Bioorg Med Chem. 5:1997;1001-1248 This timely symposium-in-print contains 25 articles especially devoted to RNA recognition by low-molecular weight ligands giving a bird's eye view of the diverse activities in present day research.
8. Pearson ND, Prescott CD. RNA as a drug target. Chem Biol. 4:1997;409-414.
9. Wallis MG, Schroeder R. The binding of antibiotics to RNA. Prog Biophys Molec Biol. 1998;. in press.
10. Chow CS, Bogdan FM. A structural basis for RNA - ligand interactions. Chem Rev. 97:1997;1489-1513.
11. Uphoff KW, Bell SD, Ellington AD. In vitro selection of aptamers: the dearth of pure reason. Curr Opin Struct Biol. 6:1996;281-288.
12. Feigon J, Dieckmann T, Smith FW. Aptamer structures from A to Z. Chem Biol. 3:1996;611-617.
13. Patel DJ, Suri AK, Jiang F, Jiang L, Fan P, Kumar RA, Nonin S. Structure, recognition and adaptive binding in RNA aptamer complexes. J Mol Biol. 272:1997;645-664.
14. Moazed S, Noller HF. Interaction of antibiotics with functional sites in 16S ribosomal RNA. Nature. 327:1987;389-394.
15. Recht MI, Fourmy D, Blanchard SC, Dahlquist KD, Puglisi JD. RNA sequence determinants for aminoglycoside binding to an A-site rRNA model oligonucleotide. of special interest J Mol Biol. 262:1996;421-436 A thorough biochemical analysis using mutational and chemical probing techniques to study the interaction of aminoglycosides with RNA oligos which are minimal models of the decoding region of 16S rRNA. Sequence differences between prokaryotic and eukaryotic 16S rRNA are uncovered that are responsible for the higher sensitivity of prokaryotes against low antibiotic concentrations.
16. Miyaguchi H, Narita H, Sakamoto K, Yokoyama S. An antibiotic-binding motif of an RNA fragment derived from the A-site-related region of Escherichia coli 16S rRNA. Nucleic Acids Res. 24:1996;3700-3706.
17. Wang Y, Hamasaki K, Rando RR. Specificity of aminoglycoside binding to RNA constructs derived from the 16S rRNA decoding region and the HIV-RRE activator region. Biochemistry. 36:1997;768-779.
18. Fourmy D, Recht MI, Blanchard SC, Puglisi JD. Structure of the A site of Escherichia coli 16S ribosomal RNA complexed with an aminoglycoside antibiotic. of oustanding interest Science. 274:1996;1367-1371 This paper describes the 3D solution structure, determined by NMR, of a complex between a model RNA derived from the A site of 16S rRNA and the aminoglycoside antibiotic paromomycin, the only complex between a non-aptamer RNA and a small effector molecule for which detailed structural information is available to date. The 3D model of the complex uncovers the structural basis for, firstly, the difference in sensitivity against low antibiotic concentrations between prokaryotic and eukaryotic 16S rRNA, and secondly, mechanisms of antibiotic resistance by site-specific methylation of the 16S rRNA in bacteria.
19. Iordanov MS, Pribnow D, Magun JL, Dinh TH, Pearson JA, Chen SLY, Magun BE. Ribotoxic stress response: activation of the stress-activated protein kinase JNK1 by inhibitors of the peptidyl transferase reaction and by sequence-specific RNA damage to the α-sarcin/ricin loop in the 28S rRNA. of special interest Mol Cell Biol. 17:1997;3373-3381 An original analysis of an unprecedented effect of the antibiotic anisomycin which induces the activation of a protein kinase by specific binding to eukaryotic 28S rRNA at concentrations where the protein biosynthesis is not impeded. The authors demonstrate that the kinase-activating signal induced by anisomycin-binding to the RNA component of active ribosomes is comparable to the effect of ribotoxic enzymes that chemically modify the 28S rRNA despite the fact that the binding site for the antibiotic is different from the recognition site of these enzymes.
20. Schroeder R, von Ahsen U. Interaction of aminoglycoside antibiotics with RNA. Nucleic Acids Mol Biol. 10:1996;53-74.
21. von Ahsen U, Davies J, Schroeder R. Antibiotic inhibition of group I ribozyme function. Nature. 353:1991;368-370.
22. Stage TK, Hertel KJ, Uhlenbeck OC. Inhibition of the hammerhead ribozyme by neomycin. RNA. 1:1995;95-101.
23. Rogers J, Chang AH, von Ahsen U, Schroeder R, Davies J. Inhibition of the self-cleavage reaction of the human hepatitis delta virus ribozyme by antibiotics. J Mol Biol. 259:1996;916-925.
24. Mei HY, Cui M, Sutton ST, Truong HN, Chung FZ, Czarnik AW. Inhibition of self-splicing group I intron RNA: high-throughput screening assays. Nucleic Acids Res. 24:1996;5051-5053.
25. Liu Y, Leibowitz MJ. Bidirectional effectors of a group I intron ribozyme. Nucleic Acids Res. 23:1995;1284-1291.
26. von Ahsen, Davies J, Schroeder R. Non-competitive inhibition of group I intron RNA self-splicing by aminoglycoside antibiotics. J Mol Biol. 226:1992;935-941.
27. Wank H, Rogers J, Davies J, Schroeder R. Peptide antibiotics of the tuberactinomycin family as inhibitors of group I intron splicing. J Mol Biol. 236:1994;1001-1010.
28. Michel F, Westhof E. Modelling of the three-dimensional architecture of group I introns based on comparative sequence analysis. J Mol Biol. 216:1990;585-610.
29. Wank H, Schroeder R. Antibiotics that interfere with RNA/RNA interactions. Green R, Schroeder R. Ribosomal RNA and Group I Introns. 1996;129-151 Chapman and Hall, New York.
30. Mei HY, Cui M, Lemrow SM, Czarnik AW. Discovery of selective, small-molecule inhibitors of RNA complexes. 2. Self-splicing group I intro ribozyme. of special interest Bioorg Med Chem. 5:1997;1185-1195 Structurally diverse compounds inhibiting self-splicing group I introns that could not have been rationally predicted were isolated by the authors using a novel high-throughput screening approach (see Mei et al. 1996 [24]).
31. Vioque A. Protein synthesis inhibitors and catalytic RNA: effect of puromycin on tRNA precursor processing by the RNA component of Escherichia coli RNase P. FEBS Lett. 246:1989;137-139.
32. Pley HW, Flaherty KM, McKay DB. Three-dimensional structure of a hammerhead ribozyme. Nature. 372:1994;68-74.
33. Scott WG, Finch JT, Klug A. The crystal structure of an all-RNA hammerhead ribozyme: a proposed mechanism for RNA catalytic cleavage. Cell. 81:1995;991-1002.
34. Clouet-d'Orval B, Stage TK, Uhlenbeck OC. Neomycin inhibition of the hammerhead ribozyme involves ionic interactions. Biochemistry. 34:1995;11186-11190.
35. Wang H, Tor Y. Electrostatic interactions in RNA-amino-glycosides binding. of special interest J Am Chem Soc. 119:1997;8734-8735 A first systematic analysis of the influence of substituents in aminoglycosides on inhibition of the hammerhead ribozyme. The authors demonstrate that the basicity of the amino substituents in the antibiotics, important for the interaction with the RNA, is modulated by neighboring hydroxyl groups. Both basicity and position of the amino substituents play a critical role in governing the eletrostatic interactions between aminoglycosides and RNA.
36. Wang H, Tor Y. RNA-aminoglycoside interactions: the design, synthesis and RNA binding of "amino-aminoglycosides" Angew Chem. 1998;. in press.
37. Hermann T, Westhof E. Aminoglycoside binding to the hammerhead ribozyme: a general model for the interaction of cationic antibiotics with RNA. of special interest J Mol Biol. 1998; A theoretical approach combining molecular modelling and dynamics simulations that puts forward the idea that high-affinity binding of aminoglycosides to RNA folds is due to a structural electrostatic complementarity between positively charged ammonium groups in the antibiotics and metal binding sites in the RNA. In the paradigm system of the hammerhead RNA, solution conformations of aminoglycosides can replace magnesium ions by engaging into interactions with the RNA virtually identical to those made by the metals in the crystal structure.
38. Wang Y, Rando RR. Specific binding of aminoglycoside antibiotics to RNA. Chem Biol. 2:1995;281-290.
39. Lato SM, Boles AR, Ellington AD. In vitro selection of RNA lectins: using combinatorial chemistry to interpret ribozyme evolution. Chem Biol. 2:1995;291-303.
40. Wallis MG, von Ahsen U, Schroeder R, Famulok M. A novel RNA motif for neomycin recognition. Chem Biol. 2:1995;543-552.
41. Famulok M, Hüttenhofer A. In vitro analysis of neomycin binding RNAs with a mutagenized pool of variants of the 16S decoding region. Biochemistry. 35:1996;4265-4270.
42. Wallis MG, Streicher B, Wank H, von Ahsen U, Clodi E, Wallace ST, Famulok M, Schroeder R. In vitro selection of a viomycin-binding RNA pseudoknot. of special interest Chem Biol. 4:1997;357-366 By comparing in vitro-selected viomycin aptamers with naturally occurring RNAs that bind the cyclic peptide antibiotic viomycin the authors could show that viomycin, needs a complex 3D RNA fold for binding.
43. Wang Y, Killian J, Hamasaki K, Rando RR. RNA molecules that specifically and stochiometrically bind aminoglycoside antibiotics with high affinities. Biochemistry. 35:1996;12338-12346.
44. Jiang L, Suri AK, Fiala R, Patel DJ. Saccharide-RNA recognition in an aminoglycoside antibiotic-RNA aptamer complex. of oustanding interest Chem Biol. 4:1996;35-50 The solution structure of an tobramycin aptamer RNA in complex with the drug, analysed by NMR spectroscopy, provides a first in-depth view of aminoglycoside-binding by RNA. Whereas at the resolution of this study it has not been possible to identify specific contacts between the aminoglycoside and the RNA, interesting features of RNA folding were uncovered showing how an almost channel-like pocket is created for the incorporation of a substrate molecule. Direct impact on the development of drugs comes from the fact that the studied tobramycin aptamer bears similarities to a conserved hexanucleotide loop in ribosomal RNA.
45. Wilson WD, 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. 32:1993;4098-4104.
46. Neault JF, Tajmir-Riahi HA. RNA-diethylstilbestrol interaction studied by Fourier transform infrared difference spectroscopy. J Biol Chem. 272:1997;8901-8904.
47. Yao S, Wilson WD. A molecular mechanics investigation of RNA complexes. I. Ethidium intercalation in an HIV-1 TAR RNA sequence with an unpaired adenosine. J Biomol Struct Dynam. 10:1992;367-387.
48. Hermann T, Heumann H. Determination of nucleotide distances in RNA by means of copper phenanthroline-generated hydroxyl radical cleavage pattern. RNA. 1:1995;1009-1017.
49. Bailly C, Colson P, Houssier C, Hamy F. The binding mode of drugs to the TAR RNA of HIV-1 studied by electric linear dichroism. Nucleic Acids Res. 24:1996;1460-1464.
50. Battigello JMA, Cui M, Roshong S, Carter BJ. Enediyne-mediated cleavage of RNA. Bioorg Med Chem. 3:1995;839-849.
51. Kappen LS, Xi Z, Goldberg IH. Effect of ribonucleotide substitution on nucleic acid bulge recognition by neocarzinostatin. Bioorg Med Chem. 5:1997;1221-1227.
52. Phe with secondary and tertiary structures by enedyine antitumor antibiotics. Bioorg Med Chem. 5:1997;1229-1234.
53. Fernandez-Saiz M, Schneider HJ, Sartorius J, Wilson WD. A cationic cyclophane that forms a base-pair open complex with RNA duplexes. J Am Chem Soc. 118:1996;4739-4745.
54. Li K, Fernandez-Saiz M, Rigl CT, Kumar A, Ragunathan KG, McConnaughie AW, Boykin DW, Schneider HJ, Wilson WD. Design and analysis of molecular motifs for specific recognition of RNA. Bioorg Med Chem. 5:1997;1157-1172.
55. Chow CS, Barton JK. Recognition of G-U mismatches by tris(4,7-diphenyl-1,10-phenanthroline)rhodium(III). Biochemistry. 31:1992;5423-5429.
56. Burgstaller P, Famulok M. Flavin-dependent photocleavage of RNA at GU base pairs. of special interest J Am Chem Soc. 119:1997;1137-1138 The authors present isoalloxazine derivatives that specifically recognize non-Watson-Crick base pairs within a helical context. The findings constitute the basis for a three-dimensional model of isoalloxazine binding to RNA presented by Burgstaller et al. 1997 [57].
57. Burgstaller P, Hermann T, Huber C, Westhof E, Famulok M. Isoalloxazine derivatives promote photocleavage of natural RNAs at G·U base pairs embedded within helices. Nucleic Acids Res. 25:1997;4018-4027.
58. Phe mediated by metal-free bleomycin. Biochemistry. 34:1995;12029-12037.
59. Holmes CE, Duff RJ, Vandermarel GA, Vanboom J, Hecht SM. On the chemistry of RNA degradation by Fe-bleomycin. Bioorg Med Chem. 5:1997;1235-1248.
60. Hurst P, Takasaki BK, Chin J. Rapid cleavage of RNA with a La(III) dimer. J Am Chem Soc. 118:1996;9982-9983.
61. Lorente A, Espinosa JF, Fernandez-Saiz M, Lehn JM, Wilson WD, Zhong YY. Syntheses of imidazole-acridine conjugates as ribonuclease A mimetics. Tetrahedron Lett. 37:1996;4417-4420.
62. Perreault DM, Cabell LA, Anslyn EV. Using guanidinium groups for the recognition of RNA and as catalysts for the hydrolysis of RNA. Bioorg Med Chem. 5:1997;1209-1220.
63. Gait MJ, Karn J. RNA recognition by the human immunodeficiency virus Tat and Rev proteins. Trends Biochem Sci. 18:1993;255-259.
64. Tao J, Frankel AD. Arginine-binding RNAs resembling TAR identified by in vitro selection. Biochemistry. 35:1996;2229-2238.
65. Harada K, Martin SS, Frankel AD. Selection of RNA-binding peptides in vivo. Nature. 380:1996;175-179.
66. Battiste JL, Mao H, Rao NS, Tan R, Muhandiral DR, Kay LE, Frankel AD, Williamson JR. α helix-RNA major groove recognition in an HIV-1 Rev peptide-RRE RNA complex. of oustanding interest Science. 273:1996;1547-1551 The solution structure solved by NMR of a peptide derived from HIV-1 Rev protein bound to Rev responsive element RNA reveals many structural details of the binding pocket in RNA formed to accommodate the α-helical peptide which penetrates deeply into a widened deep groove. A G·G base pair that was recently found to be critical for both Rev and aminoglycoside binding (Werstuck et al. 1996 [78]) is shown to play a key role for opening up the deep groove.
67. Peterson RD, Feigon J. Structural change in Rev responsive element RNA of HIV-1 on binding Rev peptide. J Mol Biol. 264:1996;863-877.
68. Ye X, Gorin A, Ellington AD, Patel DJ. Deep penetration of an α-helix into a widened RNA major groove in the HIV-1 Rev peptide-RNA aptamer complex. of oustanding interest of special interest Nat Struct Biol. 3:1996;1026-1033 NMR was used to determine the solution structure of an HIV-1 Rev-derived peptide bound to an RNA aptamer. The complex displays striking structural similarities to the Rev - Rev responsive element complex (Battiste et al. 1996 [66]) in that both RNA targets, despite their different origin, bind the α-helical peptide in the deep groove, which is widened by non-canonical purine - purine base pairs.
69. 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. 253:1995;313-332.
70. Brodsky AS, Williamson JR. Solution structure of the HIV-2 TAR-argininamide complex. of special interest J Mol Biol. 267:1997;624-639 NMR investigations on a complex of HIV-2 TAR RNA - argininamide suggest that the low-molecular-weight compound argininamide recognizes a set of structural elements in the RNA which also play a critical role in the interaction between an arginine residue of the Tat protein and TAT RNA.
71. Puglisi JD, Chen L, Blanchard S, Frankel AD. Solution structure of a bovine immunodeficiency virus Tat-TAR peptide - RNA complex. Science. 270:1995;1200-1203.
72. Ye X, Kumar RA, Patel DJ. Molecular recognition in the bovine immunodeficiency virus TAT peptide - TAR RNA complex. Chem Biol. 2:1995;827-840.
73. Ratmeyer L, Zapp ML, Green MR, Vinayak R, Kumar A, Boykin DW, Wilson WD. Inhibition of HIV-1 Rev-RRE interaction by diphenylfuran derivatives. Biochemistry. 35:1996;13689-13696.
74. Lim AC, Barton JK. Targeting the Tat-binding site of bovine immunodeficiency virus TAR RNA with a shape-selective rhodium complex. Bioorg Med Chem. 5:1997;1131-1136.
75. Mei HY, Mack DP, Galan AA, Halim NS, Heldsinger A, Loo JA, Moreland DW, Sanneslowery KA, Sharmeen L, Truong HN, Czarnik AW. Discovery of selective, small-molecule inhibitors of RNA complexes. 1. The Tat protein - TAR RNA complexes required for HIV-1 transcription. Bioorg Med Chem. 5:1997;1173-1184.
76. Mei HY, Galan AA, Halim NS, Mack DP, Moreland DW, Sanders KB, Truong HN, Czarnik AW. Inhibition of an HIV-1 Tat-derived peptide binding to TAR RNA by aminoglycoside antibiotics. Bioorg Med Chem Lett. 5:1995;2755-2760.
77. Zapp ML, Stern S, Green MR. Small molecules that selectively block RNA binding of HIV-1 Rev protein inhibit Rev function and viral production. Cell. 74:1993;969-978.
78. Werstuck G, Zapp ML, Green MR. A non-canonical base pair within the human immunodeficiency virus Rev-responsive element is involved in both Rev and small molecule recognition. Chem Biol. 3:1996;129-137.
79. Hendrix M, Priestley ES, Joyce GF, Wong CH. Direct observation of aminoglycoside-RNA interaction by surface plasmon resonance. of special interest J Am Chem Soc. 119:1997;3641-3648 The surface plasmon resonance (SPR) technique has been used to quantitatively study the interaction of various aminoglycoside antibiotics with RNA constructs mimicking the HIV-1 Rev response element. The authors demonstrate the excellent performance of SPR for rapidly screening effector compounds for their RNA-binding capacity.
80. Zapp ML, Young DW, Kumar A, Singh R, Boykin DW, Wilson WD, Green MR. Modulation of the Rev-RRE interaction by aromatic heterocyclic compounds. Bioorg Med Chem. 5:1997;1149-1155.
81. Weeks KM, Crothers DM. Major groove accessibility of RNA. Science. 261:1993;1574-1577.
82. Uhlenbeck OC, Pardi A, Feigon J. RNA structure comes of age. Cell. 90:1997;833-840.
83. Chen Q, Shafer RH, Kuntz ID. Structure-based discovery of ligands targeted to the RNA double helix. Biochemistry. 36:1997;11402-11407.
84. Hermann T, Auffinger P, Scott WG, Westhof E. Evidence for a hydroxide ion bridging two magnesium ions at the active site of the hammerhead ribozyme. Nucleic Acids Res. 25:1997;3421-3427.
85. Hermann T, Auffinger P, Westhof E. Molecular dynamics investigations on the hammerhead ribozyme RNA. Eur Biophys J. 1998;. in press.
86. Louise-May S, Auffinger P, Westhof E. Calculations of nucleic acid conformations. Curr Opin Struct Biol. 6:1996;289-298.