Methionine Sustituted Polyamides are RNAse Mimics that Inhibit Translation

RNAse mimics are small molecules that can cleave RNA in a fashion similar to ribonucleases. These compounds would be very useful as gene specific reagents if their activities could be regulated and targeted. We demonstrate here that polyamides with methionine substituents show enhanced RNA cleavage activity relative to other polyamides. Conjugation of these compounds to aminoglycosides produced RNAse mimics that are capable of inhibiting eukaryotic protein synthesis. As a new class of compounds capable of interacting with nucleic acids, these novel aminoglycoside-polyamides constitute promising scaffolds for the construction of nuclease mimics with biological activity.

[1]  Yitzhak Tor,et al.  Targeting RNA with Small Molecules , 2003, Chembiochem : a European journal of chemical biology.

[2]  J. Lown,,et al.  Synthesis and cytotoxicity evaluation of novel C7-c7, C7-N3 and N3-N3 dimers of 1-chloromethyl-5-hydroxy-1,2-dihydro-3H-benzo[e]indole (seco-CBI) with pyrrole and imidazole polyamide conjugates. , 2003, Organic & biomolecular chemistry.

[3]  J. Lown,,et al.  Synthesis and antitumor cytotoxicity evaluation of novel pyrrolo[2,1-c][1,4]benzodiazepine imidazole containing polyamide conjugates. , 2003, Oncology Research.

[4]  J. Pelletier,et al.  Forced engagement of a RNA/protein complex by a chemical inducer of dimerization to modulate gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[5]  E. Westhof,et al.  Binding of tobramycin leads to conformational changes in yeast tRNAAsp and inhibition of aminoacylation , 2002, The EMBO journal.

[6]  R. Giegé,et al.  RNase activity of a DNA minor groove binder with a minimalist catalytic motif from RNase A. , 2001, Biochemical and biophysical research communications.

[7]  V. Ramakrishnan,et al.  The Structural Basis for the Action of the Antibiotics Tetracycline, Pactamycin, and Hygromycin B on the 30S Ribosomal Subunit , 2000, Cell.

[8]  V. Vlassov,et al.  Cleavage of yeast tRNAPhe with complementary oligonucleotide conjugated to a small ribonuclease mimic , 2000, FEBS letters.

[9]  T. Giordano,et al.  RNA as a drug target: methods for biophysical characterization and screening. , 2000, Trends in biotechnology.

[10]  A. Litovchick,et al.  Aminoglycoside-arginine conjugates that bind TAR RNA: synthesis, characterization, and antiviral activity. , 2000, Biochemistry.

[11]  B. Felden,et al.  Cleavage of RNA with synthetic ribonuclease mimics. , 2000, Methods in enzymology.

[12]  J. Hughes,et al.  In vitro transport and delivery of antisense oligonucleotides. , 2000, Methods in enzymology.

[13]  E. Westhof,et al.  Aminoglycoside-RNA interactions. , 1999, Current opinion in chemical biology.

[14]  J. Basilion,et al.  Single-nucleotide polymorphisms can cause different structural folds of mRNA. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Szostak,et al.  Functional requirements for specific ligand recognition by a biotin-binding RNA pseudoknot. , 1998, Biochemistry.

[16]  R. Rando,et al.  The binding site of a specific aminoglycoside binding RNA molecule. , 1998, Biochemistry.

[17]  A. W. Czarnik,et al.  Binding of neomycin to the TAR element of HIV-1 RNA induces dissociation of Tat protein by an allosteric mechanism. , 1998, Biochemistry.

[18]  T. Klimkait,et al.  A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition. , 1998, Biochemistry.

[19]  C. Bailly,et al.  Binding of Hoechst 33258 to the TAR RNA of HIV-1. Recognition of a pyrimidine bulge-dependent structure. , 1997, Nucleic acids research.

[20]  D S Goodsell,et al.  Defining GC-specificity in the minor groove: side-by-side binding of the di-imidazole lexitropsin to C-A-T-G-G-C-C-A-T-G. , 1997, Structure.

[21]  W. Wilson,et al.  Modulation of the Rev-RRE interaction by aromatic heterocyclic compounds. , 1997, Bioorganic & medicinal chemistry.

[22]  A. W. Czarnik,et al.  Discovery of selective, small-molecule inhibitors of RNA complexes--II. Self-splicing group I intron ribozyme. , 1997, Bioorganic & medicinal chemistry.

[23]  J. Barton,et al.  Targeting the Tat-binding site of bovine immunodeficiency virus TAR RNA with a shape-selective rhodium complex. , 1997, Bioorganic & medicinal chemistry.

[24]  V. Vlassov,et al.  Sequence-specific cleavage of yeast tRNA(Phe) with oligonucleotides conjugated to a diimidazole construct. , 1997, Antisense & nucleic acid drug development.

[25]  W. Wilson,et al.  Inhibition of HIV-1 Rev-RRE interaction by diphenylfuran derivatives. , 1996, Biochemistry.

[26]  C. Bailly,et al.  The binding mode of drugs to the TAR RNA of HIV-1 studied by electric linear dichroism. , 1996, Nucleic acids research.

[27]  W. Wilson,et al.  Design and analysis of RNA structure‐specific agents as potential antivirals , 1996, Journal of molecular recognition : JMR.

[28]  B. Felden,et al.  Cleavage of tRNA with imidazole and spermine imidazole constructs: a new approach for probing RNA structure. , 1995, Nucleic acids research.

[29]  V. Vlassov,et al.  Synthetic RNA-cleaving molecules mimicking ribonuclease A active center. Design and cleavage of tRNA transcripts. , 1993, Nucleic acids research.

[30]  W. Wilson,et al.  A molecular mechanics investigation of RNA complexes. I. Ethidium intercalation in an HIV-1 TAR RNA sequence with an unpaired adenosine. , 1992, Journal of biomolecular structure & dynamics.

[31]  M. Leibowitz,et al.  Design of peptide-acridine mimics of ribonuclease activity , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[32]  D. Sigman,et al.  Chemical nucleases. , 1990, Biochemistry.

[33]  E. Anslyn,et al.  On the mechanism of action of ribonucleases: dinucleotide cleavage catalyzed by imidazole and Zn2+. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. Kauten,et al.  Inhibition of mammalian microsomal protein synthesis by aminoglycoside antibiotics. , 1984, Journal of Antimicrobial Chemotherapy.

[35]  M. Loveless,et al.  The influence of aminoglycoside antibiotics on the in vitro function of rat liver ribosomes. , 1984, Journal of Laboratory and Clinical Medicine.

[36]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .