Negamycin Analogue with Readthrough-Promoting Activity as a Potential Drug Candidate for Duchenne Muscular Dystrophy

Taguchi, Akihiro; Nishiguchi, Shigenobu; Shiozuka, Masataka; Nomoto, Takao; Ina, Mayuko; Nojima, Shouta; Matsuda, Reiko; Nonomura, Yoshiaki; Kiso, Yoshiaki; Yamazaki, Yoshihiro; Yakushiji, Fumika; Hayashi, Yoshio

doi:10.1021/ml200245t

Cited by 22 publications

(17 citation statements)

References 22 publications

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“…Some examples of bioactive and derivative compounds are shown in Figure 1: (−)-sedamine (Figure 1A), used for the treatment of cognitive disorders, 16 the antidepressant drug fluoxetine (Figure 1B), 17 and (+)-negamycin (Figure 1C), which are used for the treatment of muscular dystrophy. 18 Theoretical and experimental studies have reported on IHBs in 1,3-disubstituted acyclic amino alcohols. However, most of these studies are carried out either only in the gas phase or in a single solvent.…”

Section: Introductionmentioning

confidence: 99%

Dealing with Hydrogen Bonding on the Conformational Preference of 1,3-Aminopropanols: Experimental and Molecular Dynamics Approaches

et al. 2019

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This study expands the knowledge on the conformational preference of 1,3-amino alcohols in the gas phase and in solution. By employing Fourier transform infrared spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, density functional theory (DFT) calculations, quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO) analysis, and molecular dynamics (MD), the compounds 3-aminopropan-1-ol (1), 3-methylaminopropan-1-ol (2), and 3-dimethylaminopropan-1-ol (3) are evaluated. The results show that the most stable conformation of each compound in the gas phase and in nonpolar solvents exhibited an O–H···N intramolecular hydrogen bond (IHB). Based on the experimental and theoretical OH-stretching frequencies, the IHB becomes stronger from 1 to 3. In addition, from the experimental NMR J-couplings, the IHB conformers are predominant in nonbasic solvents, representing 70–80% of the conformational equilibrium, while in basic solvents, such conformers only represent 10%. DFT calculations and QTAIM analysis in the gas phase support the occurrence of IHBs in these compounds. The MD simulation indicates that the non-hydrogen-bonded conformers are the lowest energy conformations in the solution because of molecular interactions with the solvent, while they are absent in the implicit solvation model based on density. NBO analysis suggests that methyl groups attached on the nitrogen atom affect the charge transfer energy involved in the IHB. This effect occurs mostly because of a decrease in the s-character of the LPN orbital along with weakening of the charge transfer from LPN to σ*OH, which is caused by an increase in the C–C–N bond angle.

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Section: Introductionmentioning

confidence: 99%

Dealing with Hydrogen Bonding on the Conformational Preference of 1,3-Aminopropanols: Experimental and Molecular Dynamics Approaches

et al. 2019

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“…The putative miscoding activity of NEG has made it an appealing candidate for the treatment of human genetic disorders caused by nonsense mutations. NEG or its synthetic analogs have demonstrated promising activity in stimulating premature stop codon bypass and partially restoring expression of several disease-related genes inactivated by nonsense mutations (Allamand et al, 2008; Arakawa et al, 2003; Floquet et al, 2011; Taguchi et al, 2012). These findings have made the need to uncover the site and the mode of action of NEG even more compelling.…”

Section: Introductionmentioning

confidence: 99%

Negamycin Interferes with Decoding and Translocation by Simultaneous Interaction with rRNA and tRNA

et al. 2014

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SUMMARY Negamycin (NEG) is a ribosome targeting antibiotic which exhibits clinically promising activity. Its binding site and mode of action have remained unknown. We solved the structure of the Thermus thermophilus ribosome bound to mRNA and three tRNAs, in complex with NEG. The drug binds to both small and large ribosomal subunits at 9 independent sites. Resistance mutations in the 16S rRNA unequivocally identified the binding site in the vicinity of the conserved helix 34 (h34) in the small subunit as the primary site of antibiotic action in the bacterial and, possibly, eukaryotic ribosome. At this site, NEG contacts 16S rRNA as well as the anticodon loop of the A-site tRNA. Although the NEG site of action overlaps with that of tetracycline (TET), the two antibiotics exhibit different activities: while TET sterically hinders binding of aminoacyl-tRNA to the ribosome, NEG stabilizes its binding thereby inhibiting translocation and stimulating miscoding.

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“…To overcome these limitations, structurally designed aminoglycosides with reduced nephrotoxicity and ototoxicity that maintain readthrough activity have been developed ( Shulman et al., 2014 ; Xue et al., 2014 ). In addition, non-aminoglycoside PTC readthrough compounds have been identified by high-throughput library screening ( Du et al., 2009 ; Kayali et al., 2012 ), and some have been chemically modified to improve activity ( Hamada et al., 2019 ; Taguchi et al., 2012 , 2017 ). In addition, several compounds have been found to enhance the activity of PTC readthrough compounds, allowing the use of reduced doses of aminoglycosides and thus reduced toxicity ( Baradaran-Heravi et al., 2016 ; Ferguson et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

NanoLuc reporters identify COL4A5 nonsense mutations susceptible to drug-induced stop codon readthrough

et al. 2022

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Negamycin Analogue with Readthrough-Promoting Activity as a Potential Drug Candidate for Duchenne Muscular Dystrophy

Cited by 22 publications

References 22 publications

Dealing with Hydrogen Bonding on the Conformational Preference of 1,3-Aminopropanols: Experimental and Molecular Dynamics Approaches

Dealing with Hydrogen Bonding on the Conformational Preference of 1,3-Aminopropanols: Experimental and Molecular Dynamics Approaches

Negamycin Interferes with Decoding and Translocation by Simultaneous Interaction with rRNA and tRNA

NanoLuc reporters identify COL4A5 nonsense mutations susceptible to drug-induced stop codon readthrough

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