Ligand‐Assisted Complex Formation of Two DNA Hairpin Loops

Hong, Changfeng; Hagihara, Masaki; Nakatani, Kazuhiko

doi:10.1002/ange.201100075

Cited by 4 publications

(3 citation statements)

References 28 publications

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“…The ( Z )-stilbene linker in Z -NCTS was designed to place the naphthyridines in preorganized positions appropriate for the binding. Synthesis of NCT (22) and Z -NCTS was achieved by reductive amination of glutaraldehyde and ( Z )-4,4′-diformylstilbene (47), respectively, with the secondary amino group of NCD (Scheme 1). NCTB and E -NCTS were synthesized from 3,3′-bis(bromomethyl)biphenyl (48) and ( E )−4,4′-bis(bromomethyl)stilbene (49) using a nucleophilic substitution reaction with two NCD molecules.…”

Section: Resultsmentioning

confidence: 99%

“…Although we have reported that NT and NCT containing flexible methylene linkers could uniquely interact with human telomeric repeats d(TTAGGG) n (21) and DNA hairpin loops (22), respectively, their interactions with DNA GG mismatches remained to be studied. Thermal melting experiments showed that both NT and NCT increased the T m of DNA containing a CGG/CGG sequence by 13.5°C and 18.7°C, respectively (Figure 3a).…”

Section: Discussionmentioning

confidence: 99%

“…Pyrrole–imidazole polyamide is a sequence-specific DNA binder rationally developed from natural minor groove binders, and has been studied for the regulation of gene expression and applied to DNA nanotechnology (1–3). Besides the sequence-specific ligands for regular double-stranded DNA, much effort has been devoted to develop artificial ligands targeting a variety of local DNA and RNA structures (4–27), such as multistranded helices (4–6), bulges (12,26), mismatches (9–13), loops (22), and repetitive motifs (15–17,25). Since these local structures are related closely to natural and artificial functions of nucleic acids, ligands binding to the structures are useful molecular tools for detection and control of the functions.…”

Section: Introductionmentioning

confidence: 99%

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Naphthyridine tetramer with a pre-organized structure for 1:1 binding to a CGG/CGG sequence

Dohno

Koyanagi

Hong

et al. 2011

Nucleic Acids Research

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A naphthyridine carbamate dimer (NCD) is a synthetic ligand for DNA containing a CGG/CGG sequence. Although NCD can bind selectively and tightly to a CGG/CGG sequence, the highly cooperative 2:1 binding mode has hampered precise analysis of the binding. We describe herein the synthesis of a series of naphthyridine tetramers consisting of two NCD molecules connected with various linkers to seek a ligand that binds to a CGG/CGG sequence exclusively with a 1:1 stoichiometry. Among the tested ligands, NCTB and Z-NCTS, which have linker moieties with restricted conformational flexibility [biphenyl and (Z)-stilbene linker, respectively], gave the exclusive formation of a 1:1 ligand–CGG/CGG complex. The (Z)-stilbene linker in Z-NCTS was designed to have pre-organized conformation appropriate for the binding and, in fact, resulted in the highest binding affinity. Thermodynamic parameters obtained by isothermal titration calorimetry indicated that the stronger binding of Z-NCTS was attributed to its lower entropic cost. The present study provides not only a novel 1:1 binding ligand, but also valuable feedback for subsequent molecular design of DNA and RNA binding ligands.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Naphthyridine tetramer with a pre-organized structure for 1:1 binding to a CGG/CGG sequence

Dohno

Koyanagi

Hong

et al. 2011

Nucleic Acids Research

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¹⁹F NMR‐Based Fragment Screening for 14 Different Biologically Active RNAs and 10 DNA and Protein Counter‐Screens

et al. 2020

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We report here on the nuclear magnetic resonance (NMR) 19 F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter‐screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow‐up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low micromolar binding affinity without losing binding specificity between two different terminator structures.

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Formation of a Ligand‐Assisted Complex of Two RNA Hairpin Loops

Hong¹,

Otabe²,

Matsumoto³

et al. 2014

Chemistry A European J

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The hairpin structure is one of the most common secondary structures in RNA and holds a central position in the stream of RNA folding from a non-structured RNA to structurally complex and functional ribonucleoproteins. Since the RNA secondary structure is strongly correlated to the function and can be modulated by the binding of small molecules, we have investigated the modulation of RNA folding by a ligand-assisted formation of loop-loop complexes of two RNA hairpin loops. With a ligand (NCT6), designed based on the ligand binding to the G-G mismatches in double-stranded DNA, we successfully demonstrated the formation of both inter- and intra-molecular NCT6-assisted complex of two RNA hairpin loops. NCT6 selectively bound to the two hairpin loops containing (CGG)3 in the loop region. Native polyacrylamide gel electrophoresis analysis of two doubly-labeled RNA hairpin loops clearly showed the formation of intermolecular NCT6-assisted loop-loop complex. Förster resonance energy-transfer studies of RNA constructs containing two hairpin loops, in which each hairpin was labeled with Alexa488 and Cy3 fluorophores, showed the conformational change of the RNA constructs upon binding of NCT6. These experimental data showed that NCT6 simultaneously bound to two hairpin RNAs at the loop region, and can induce the conformational change of the RNA molecule. These data strongly support that NCT6 functions as molecular glue for two hairpin RNAs.

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Ligand‐Assisted Complex Formation of Two DNA Hairpin Loops

Cited by 4 publications

References 28 publications

Naphthyridine tetramer with a pre-organized structure for 1:1 binding to a CGG/CGG sequence

Naphthyridine tetramer with a pre-organized structure for 1:1 binding to a CGG/CGG sequence

¹⁹F NMR‐Based Fragment Screening for 14 Different Biologically Active RNAs and 10 DNA and Protein Counter‐Screens

Formation of a Ligand‐Assisted Complex of Two RNA Hairpin Loops

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Ligand‐Assisted Complex Formation of Two DNA Hairpin Loops

Cited by 4 publications

References 28 publications

Naphthyridine tetramer with a pre-organized structure for 1:1 binding to a CGG/CGG sequence

Naphthyridine tetramer with a pre-organized structure for 1:1 binding to a CGG/CGG sequence

19F NMR‐Based Fragment Screening for 14 Different Biologically Active RNAs and 10 DNA and Protein Counter‐Screens

Formation of a Ligand‐Assisted Complex of Two RNA Hairpin Loops

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¹⁹F NMR‐Based Fragment Screening for 14 Different Biologically Active RNAs and 10 DNA and Protein Counter‐Screens