Structure—Activity Studies of Oxazolidinone Analogues as RNA-Binding Agents.

Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.42). 08/2006; 16(13):3600-4. DOI: 10.1016/j.bmcl.2006.03.068
Source: PubMed


We have synthesized and tested a series of novel 3,4,5-tri- and 4,5-disubstituted oxazolidinones for their ability to bind two structurally related T box antiterminator model RNAs. We have found that optimal binding selectivity is found in a small group of 4,5-disubstituted oxazolidinones.

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    • "Aminoglycosides bind AM1A in a structure-specific manner, most likely via electrostatics [13,14]. In contrast, two novel classes of heterocyclic compounds, triazoles and oxazolidinones, bind AM1A with structure-specificity and high affinity, but without reliance on electrostatics [15-18] and can alter T box transcription antitermination [16]. A computational, quantitative structure activity relationship analysis has shown that hydrophobic interactions play a significant role in the binding of these compounds to AM1A [19]. "
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    ABSTRACT: The T box riboswitch controls bacterial transcription by structurally responding to tRNA aminoacylation charging ratios. Knowledge of the thermodynamic stability difference between two competing structural elements within the riboswitch, the terminator and the antiterminator, is critical for effective T box-targeted drug discovery. The ΔG of aminoacyl tRNA synthetase (aaRS) T box riboswitch terminators and antiterminators was predicted using DINAMelt and the resulting ΔΔG (ΔG Terminator - ΔG Antiterminator) values were compared. Average ΔΔG values did not differ significantly between the bacterial species analyzed, but there were significant differences based on the type of aaRS. The data indicate that, of the bacteria studied, there is little potential for drug targeting based on overall bacteria-specific thermodynamic differences of the T box antiterminator vs. terminator stability, but that aaRS-specific thermodynamic differences could possibly be exploited for designing drug specificity.
    BMC Bioinformatics 03/2012; 13 Suppl 2(Suppl 2):S5. DOI:10.1186/1471-2105-13-S2-S5 · 2.58 Impact Factor
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    • "Antiterminator and tRNA model RNAs. (B) 2-AP-AM1A; (C) 9-AP-AM1A [30]; (D) 10-AP-AM1A; (E) 13-AP-AM1A; (F) tRNA- UCCA [28]; (G) mh-UCCA [28] and mh-ACCA [28]. "
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    ABSTRACT: The T box transcription antitermination riboswitch is one of the main regulatory mechanisms utilized by Gram-positive bacteria to regulate genes that are involved in amino acid metabolism. The details of the antitermination event, including the role that Mg2+ plays, in this riboswitch have not been completely elucidated. In these studies, details of the antitermination event were investigated utilizing 2-aminopurine to monitor structural changes of a model antiterminator RNA when it was bound to model tRNA. Based on the results of these fluorescence studies, the model tRNA binds the model antiterminator RNA via an induced-fit. This binding is enhanced by the presence of Mg2+, facilitating the complete base pairing of the model tRNA acceptor end with the complementary bases in the model antiterminator bulge.
    Biochemical and Biophysical Research Communications 11/2009; 389(4-389):616-621. DOI:10.1016/j.bbrc.2009.09.037 · 2.30 Impact Factor
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    • "Compound 3, identified from a spot to which neither RNA bound, was made and tested in solution binding assays for comparison. Binding of ligands to the RNA hairpins in solution was assessed using the base analogue 2-ap as a fluorescent probe (43,44). The fluorescent base was substituted for the adenine indicated in Figure 2, and the peptoid-dependent change in fluorescence was used to determine the dissociation constant (Figure 4). "
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    ABSTRACT: We have screened peptoid microarrays to identify specific ligands for the RNA hairpin precursor of miR-21, a microRNA involved in cancer and heart disease. Microarrays were printed by spotting a library of 7680 N-substituted oligoglycines (peptoids) onto glass slides. Two compounds on the array specifically bind RNA having the sequence and predicted secondary structure of the miR-21 precursor hairpin and have specific affinity for the target in solution. Their binding induces a conformational change around the hairpin loop, and the most specific compound recognizes the loop sequence and a bulged uridine in the proximal duplex. Functional groups contributing affinity and specificity were identified, and by varying a critical methylpyridine group, a compound with a dissociation constant of 1.9 microM for the miR-21 precursor hairpin and a 20-fold discrimination against a closely-related hairpin was created. This work describes a systematic approach to discovery of ligands for specific pre-defined novel RNA structures. It demonstrates discovery of new ligands for an RNA for which no specific lead compounds were previously known by screening a microarray of small molecules.
    Nucleic Acids Research 07/2009; 37(16):5486-97. DOI:10.1093/nar/gkp549 · 9.11 Impact Factor
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