Structure-based and combinatorial search for new RNA-binding drugs

Current Opinion in Biotechnology

Volumn 10, Issue 1, 1999, Pages 59-63

  Afshar, Mohammad ^a   Prescott, Catherine D ^a   Varani, Gabriele ^b  

^a Ribotargets Ltd   (United Kingdom)

^b MRC LABORATORY OF MOLECULAR BIOLOGY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT;

ASSAY; DRUG BINDING SITE; DRUG SPECIFICITY; DRUG TARGETING; PRIORITY JOURNAL; REVIEW; RNA STRUCTURE; STRUCTURE ACTIVITY RELATION;

BACTERIA (MICROORGANISMS);

EID: 0032959541     PISSN: 09581669     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0958-1669(99)80011-1     Document Type: Article

References (47)

1. Fan P, Suri AK, Fiala R, Live D, Patel DJ Molecular recognition in the FMN-RNA aptamer complex. J Mol Biol. 258:1996;480-500.
2. Jiang F, Kumar RA, Jones RA, Patel DJ Structural basis of RNA folding and recognition in an AMP-RNA aptamer complex. Nature. 382:1996;183-186.
3. Yang Y, Kochoyan M, Burgstaller P, Westhof E, Famulok M Structural basis of ligand discrimination by two related RNA aptamers resolved by NMR spectroscopy. Science. 272:1996;1343-1347.
4. Zimmermann GR, Jenison RD, Wick CL, Simorre J-P, Pardi A Interlocking structural motifs mediate molecular discrimination by a theophylline-binding RNA. Nat Struct Biol. 4:1997;644-649. An RNA aptamer selected in vitro to bind theophylline but not related molecules (e.g. caffeine) was much more effective at molecular discriminaton than monoclonal antibodies. This work reveals the structural basis for this high-resolution molecular discrimination.
5. Dieckmann T, Suzuki E, Nakamura GK, Feigon J Solution structure of an ATP-binding RNA aptamer reveals a novel fold. RNA. 2:1996;628-640.
6. Fourmy D, Recht MI, Blanchard SC, Puglisi JD Structure of the A site of Escherichia coli 16S ribosomal RNA complexed with an aminoglycoside antibiotic. Science. 274:1996;1367-1371.
7. •].
8. •] present structures of aminoglycoside antibiotics in complex with RNA aptamers selected to bind them. Although these are examples of the 'inverse-recognition' problem, this work contributes to a growing understanding of the structural principles underlying RNA-small-molecule recognition.
9. •].
10. •], build upon the structure of paromomycin-ribosomal RNA complex to dissect the thermodynamic basis of ribosomal RNA recognition by aminoglycoside antibiotics.
11. Recht MI, Fourmy D, Blanchard SC, Dahlquist KD, Puglisi JD RNA sequence determinants for aminoglycoside binding to an A-site rRNA model oligonucleotide. J Mol Biol. 262:1996;421-436.
12. 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. Proc Natl Acad Sci USA. 94:1997;3548-3553. Deconvolution of a combinatorial peptoidic library led to the identification and structural characterization of a compound that inhibits Tat binding to HIV-1 TAR RNA. This was the first compound found to inhibit viral replication in cell-based assays by binding its cognate RNA target.
13. Hamy F, Brondani V, Flörsheimer A, Stark W, Blommers MJJ, Klimkait T A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition. Biochemistry. 37:1998;5086-5095. Characterization by SAR methods and NMR of a class of acridine derivatives found to bind TAR RNA and inhibit Tat binding to it.
14. 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.
15. Wang S, Huber PW, Cui M, Czarnik AW, Mei H-Y Binding of neomycin to TAR element of HIV-1 RNA induces dissociation of Tat protein by an allosteric mechanism. Biochemistry. 37:1998;5549-5557. Aminoglycoside antibiotic neomycin binds the minor groove of TAR RNA and inhibits Tat-protein binding by an allosteric mechanism.
16. Rosenfeld R, Vajda S, DeLisi C Flexible docking and design. Annu Rev Biophys Biomol Struct. 24:1995;677-700.
17. Janin J Elusive affinities. Proteins. 21:1995;30-39.
18. Cummings MD, Hart TN, Read RJ Atomic solvation parameters in the analysis of protein-protein docking results. Protein Sci. 4:1995;2087-2099.
19. Bohm HJ The development of a simple scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Comput Aided Mol Des. 8:1994;243-256.
20. Chen Q, Shafer RH, Kuntz ID Structure-based discovery of ligands targeted to the RNA double helix. Biochemistry. 36:1997;11402-11407. The DOCK suite of drug discovery programs is used for the first time in the context of RNA-based drug discovery to search for new double-helical RNA binding drugs.
21. Wang H, Tor Y Electrostatic interactions in RNA aminoglycosides binding. J Am Chem Soc. 119:1997;8734-8735. An investigation by SAR methods of aminoglycoside-RNA interaction reveals that much of the binding energy is derived from electrostatic interactions.
22. Leclerc F, Cedergren R Modelling RNA-ligand interactions: the Rev-binding element RNA-aminoglycoside complex. J Med Chem. 41:1998;175-182.
23. •].
24. •]) and experimental methods suggest strongly that the ability of aminoglycoside antibiotics to inhibit RNA enzymes is due to the displacement of RNA-bound divalent metal ions.
25. ••].
26. ••], reports on the development of new assays to obtain quantitative SAR data for aminoglycoside-RNA interaction. This work provides very valuable information for the design of synthetically accessible analogs of this important class of antibiotics.
27. Jain C, Belasco JG A structural model for the HIV-1 Rev-RRE complex deduced from altered specificity Rev variants isolated by rapid genetic strategy. Cell. 87:1996;115-125.
28. Friesen WJ, Darby MK Specific RNA binding proteins constructed from zinc fingers. Nat Struct Biol. 5:1998;543-546.
29. Harada K, Martin SS, Frankel AD Selection of RNA-binding peptides in vivo. Nature. 380:1996;175-179.
30. Paraskeva E, Atzberger A, Hentze MW A translational repression assay procedure (TRAP) for RNA-protein interactions in vivo. Proc Natl Acad Sci USA. 95:1998;951-956.
31. Thon G, Prescott CD The selection and characterization of an RNA recognition motif for spectinomycin. Bioorg Med Chem. 5:1997;1081-1086.
32. Wang Y, Killian J, Hamasaki K, Rando RR RNA molecules that specifically and stoichiometrically bind aminoglycoside antibiotics with high affinity. Biochemistry. 35:1996;12338-12346.
33. ••].
34. Mei H-Y, 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. 22:1995;2755-2760.
35. Park WKC, Auer M, Jaksche H, Wong C-H 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. J Am Chem Soc. 118:1996;10150-10155.
36. ••].
37. ••], reports on RNA binding by smaller aminoglycoside mimetics, introducing the possibility of mimicking aminoglycoside-RNA binding with much smaller and synthetically more accessible scaffolds.
38. •].
39. •].
40. •], reports on RNA binding by polycationic compounds presented on relatively rigid scaffolds. Submicromolar binding to HIV-1 TAR RNA in a mixed library was observed in this study.
41. Mei H-Y, Cui M, Sutton ST, Truong HN, Chung F-Z, Czarnik AW Inhibition of self-splicing group I intron RNA: high-throughout screening assays. Nucleic Acids Res. 24:1996;5051-5053.
42. Mei H-Y, Cui M, Lemrow SM, Czarnik AW Discovery of selective, small-molecule inhibitors of RNA complexes-II. Self-splicing group I intron ribozyme. Bioorg Med Chem. 5:1997;1185-1195. Discovery of small molecular weight inhibitors of RNA enzymes by high-throughput analysis of a large proprietary library. This work could provide leads in the discovery of novel antifungal compounds that target the activity of these RNA enzymes encoded by the genome of some of these organisms.
43. Bachelin M, Hessler G, Kurz G, Hacia JG, Dervan PB, Kessler H Structure of a stereoregular phosphorothioate DNA-RNA Duplex. Nat Struct Biol. 5:1998;271-276. The structure of a stereoregular phosphorothioate DNA-RNA hybrid reveals the similarity in structure with unmodified DNA-RNA hybrids, providing a structural basis for the sensitivity to RNAseH and the high thermal stability of phosphorothioate-substituted DNA-RNA duplexes.
44. Branch AD A good antisense molecule is hard to find. Trends Biochem Sci. 23:1998;45-50.
45. Uhlenbeck OC, Pardi A, Feigon J RNA structure comes of age. Cell. 90:1997;833-840.
46. Testa SM, Gryaznov SM, Turner DH Antisense binding enhanced by teriary interactions: binding of phosphorothioate and N3′-P5′ phosphoramidate hexanucleotides to the catalytic core of a group I ribozyme from the mammalian pathogen Pneumocystis carinii. Biochemistry. 37:1994;9379-9385. An interesting new approach to antisense-based inhibition of RNA enzymes is provided by the stabilization of interactions specific to antisense by tertiary binding at the active site of the ribozyme.
47. Purohit P, Stern S Interactions of a small RNA with antibiotic and RNA ligands of the 30S subunit. Nature. 370:1994;659-662.