Modified Intercalation Model for the Interaction of Amino Acridines and DNA

Pritchard, N. J.; Blake, Allan D.; Peacocke, A. R.

doi:10.1038/2121360a0

Cited by 199 publications

(59 citation statements)

References 13 publications

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“…Some properties of QC and 9AA that likely contribute to their biological activities have been identified. It has been well documented that both QC and 9AA can intercalate into double-stranded DNA and structured RNA molecules (31,34,44) and are capable of inhibiting DNA replication, RNA transcription, and protein synthesis (7,10,26,29). The extent of intercalation of QC into RNA molecules depends on the complexity of RNA secondary and tertiary structures (such as hairpin loops that produce regions of double-stranded RNA) and pseudoknots (2,52).…”

mentioning

confidence: 99%

Inhibition of Encephalomyocarditis Virus and Poliovirus Replication by Quinacrine: Implications for the Design and Discovery of Novel Antiviral Drugs

Gasparian

Neznanov

Jha

et al. 2010

J Virol

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The 9-aminoacridine (9AA) derivative quinacrine (QC) has a long history of safe human use as an antiprotozoal and antirheumatic agent. QC intercalates into DNA and RNA and can inhibit DNA replication, RNA transcription, and protein synthesis. The extent of QC intercalation into RNA depends on the complexity of its secondary and tertiary structure. Internal ribosome entry sites (IRESs) that are required for initiation of translation of some viral and cellular mRNAs typically have complex structures. Recent work has shown that some intercalating drugs, including QC, are capable of inhibiting hepatitis C virus IRES-mediated translation in a cell-free system. Here, we show that QC suppresses translation directed by the encephalomyocarditis virus (EMCV) and poliovirus IRESs in a cell-free system and in virus-infected HeLa cells. In contrast, IRESs present in the mammalian p53 transcript that are predicted to have less-complex structures were not sensitive to QC. Inhibition of IRES-mediated translation by QC correlated with the affinity of binding between QC and the particular IRES. Expression of viral capsid proteins, replication of viral RNAs, and production of virus were all strongly inhibited by QC (and 9AA). These results suggest that QC and similar intercalating drugs could potentially be used for treatment of viral infections.

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mentioning

confidence: 99%

Inhibition of Encephalomyocarditis Virus and Poliovirus Replication by Quinacrine: Implications for the Design and Discovery of Novel Antiviral Drugs

Gasparian

Neznanov

Jha

et al. 2010

J Virol

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“…It is known, however. that denaturation of DNA does not reduce substantially the binding of the drugs; this has led to the proposal of a modified intercalation model which involves overlap between the aromatic rings of the drugs and those of adjacent bases on the same polynucleotide chain (Pritchard et a/., 1966).…”

Section: Interaction With Dnamentioning

confidence: 99%

Interaction of Acridine Drugs With Dna and Nucleotides

Georghiou

1977

Photochem & Photobiology

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Abstract-At high phosphate-to-drug ratios acridine drugs intercalate between hydrogen bonded DNA base pairs causing significant changes in the physico-chemical properties of DNA. The determination of the nature of the strong (or primary) interaction between acridine drugs and DNA is of great importance for elucidating the mode of the biological action of the drugs.Nanosecond measurements have revealed a fast depolarization of the fluorescence of proflavine, one of the most extensively studied acridines, bound to DNA. The electronic structure of the complex, however, is not substantially altered during the lifetime of the excited singlet electronic state of the drug. Guanine has been shown to be responsible for the quenching of the proflavine fluorescence upon binding to DNA. A temperature-jump relaxation study has demonstrated a rather external complexation of this drug with the G-C base pairs; this complex, whose formation occurs in the strong binding region, is distinct from the weak electrostatic complex.The findings that the binding ability of a series of acridines correlates with their basicity and that the drug-binding behavior of methylated DNA is significantly different from that of DNA suggested that specific forces may be also involved in the drug-DNA binding in addition to hydrophobic forces. Recent experiments employing molecular complexes of acridines with nucleotides as model systems have provided strong support for the specificity of the drug-DNA interaction. Hydrogen bonding between the drug and reactive groups of the DNA bases that do not contribute directly to the stability of the helix may be involved in that interaction.The stoichiometry of the proflavine-guanosine 5'-phosphate complex is 1 : 1. Its association constant increases from 310 M -' , when proflavine is in its ground electronic state, to 1550 M -' , when proflavine is in its first excited singlet state. Thus, light absorbed by the drug alters its reactivity which, in turn, results in an appreciable increase in its ability to bind to the nucleotide. In view of the proposed importance of the drug-base interaction in explaining the mutagenic properties of acridine drugs and, in particular, of the proposed involvement of the G-C base pairs, this finding emphasizes the possible importance of drug photoexcitation in acridine mutagenesis; it also contributes to the elucidation of photodynamic action.X-ray diffraction studies have recently provided very interesting demonstrations of strong binding of 9-aminoacridine and of the phenanthridine drug ethidium bromide to adenine-uracil base pairs in the crystalline phase.The ability of photoexcited acridine drugs to inactivate viruses has been recently used for therapeutic purposes. The carcinogenic risk involved, however, is still under investigation.

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“…The results presented here can principally give us information about the orientation of the dye molecules in the complex [ 171, and in any case show that the configuration of the DNA-PF complex deviates from that which had been proposed in the initial model of intercalation [19] and probably from those which were proposed later by Fuller and Waring [2 1 ] and Prichard, Blake and Peacock [22].…”

Section: Resultsmentioning

confidence: 75%

Circular dichroism of flow‐oriented DNA—proflavine complex

Poletayev

1976

FEBS Letters

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Modified Intercalation Model for the Interaction of Amino Acridines and DNA

Cited by 199 publications

References 13 publications

Inhibition of Encephalomyocarditis Virus and Poliovirus Replication by Quinacrine: Implications for the Design and Discovery of Novel Antiviral Drugs

Inhibition of Encephalomyocarditis Virus and Poliovirus Replication by Quinacrine: Implications for the Design and Discovery of Novel Antiviral Drugs

Interaction of Acridine Drugs With Dna and Nucleotides

Circular dichroism of flow‐oriented DNA—proflavine complex

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