Recent developments in compounds acting in the DNA minor groove

Rahman, Adeyemi; O’Sullivan, Patrick; Rozas, Isabel

doi:10.1039/c8md00425k

Cited by 65 publications

(46 citation statements)

References 88 publications

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“…Pentamidine has also been used to prevent and treat opportunistic pneumonia that is caused by Pneumocystis carinii which is common in AIDS patients.. The drugs have found additional applications in clinical medicine including use as general antitumor, antibacterial and antiviral agents (12,(35)(36)(37)(38). However, the targets and modes of action of the drugs remain, for the most part, unknown.…”

Section: Dicussionmentioning

confidence: 99%

“…Likewise, to our knowledge, MGBDs have not been tested for activity against simian immunodeficiency viruses or the lentiviruses that infect nonprimate mammals, though the nucleotide composition of these viral genomes are nearly identical to that of HIV-1 (8). Much more emphasis has been devoted to the synthesis of distamycin conjugates and analogues as anti-HIV drugs with the goal of targeting the ligands to defined features of the viral life cycle (12). For example, several distamycin-related polyanionic conjugates are inhibitors of HIV-induced cell killing and mechanistic studies suggest that the inhibition is due to the inhibition of virus attachment to CD4+ susceptible cells (40).…”

Section: Dicussionmentioning

confidence: 99%

“…In addition, in contrast to many of the MGBDs, berenil and pentamidine display low toxicity and both drugs have been reported to be non mutagenic in mammalian cells (48)(49)(50). Distamycin and Hoechst 33258 have most often served as the starting point for synthesis of most MGBD conjugates and analogs (12,49). A similar approach could be adopted for the synthesis of conjugates of the structurally simpler drugs such as berenil, pentamidine, or DAPI in order to optimize the specificity of these compounds for the clustered AT-sites in the HIV genome.…”

Section: Dicussionmentioning

confidence: 99%

“…The minor groove binding drugs (MGBDs) are of interest in clinical medicine because of their antiviral, antimicrobial and antitumor activities (10)(11)(12). These ligands preferentially bind to AT-rich DNA sequences that are 4 or more bp in length.…”

Section: Introductionmentioning

confidence: 99%

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HIV chromatin is a preferred target for drugs that bind in the DNA minor groove

Little

Schäfer

Anderson³

2019

Preprint

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The HIV genome is rich in A but not G or U and deficient in C. This nucleotide bias controls HIV phenotype by determining the highly unusual composition of all majors HIV proteins. Since drugs that bind in the DNA minor groove disrupt nucleosomes on sequences that contain closely spaced oligo-A tracts which are prevalent in HIV DNA because of this bias, it was of interest to determine if these drugs exert this selective inhibitory effect on HIV chromatin.To test this possibility, nucleosomes were reconstituted onto five double-stranded DNA fragments from the HIV-1 pol gene in the presence and in the absence of several minor groove binding drugs (MGBDs). The results demonstrated that the MGBDs inhibited the assembly of nucleosomes onto all of the HIV-1 segments in a manner that was proportional to the A-bias, but had no detectable effect on the formation of nucleosomes on control cloned fragments or genomic DNA from chicken and human. Nucleosomes preassembled onto HIV DNA were also preferentially destabilized by the drugs as evidenced by enhanced nuclease accessibility in physiological ionic strength and by the preferential loss of the histone octamer in hyperphysiological salt solutions. The drugs also selectively disrupted HIV-containing nucleosomes in yeast as revealed by enhanced nuclease accessibility of the in vivo assembled HIV chromatin and reductions in superhelical densities of plasmid chromatin containing HIV sequences. A comparison of these results to the density of A-tracts in the HIV genome indicates that a large fraction of the nucleosomes that make up HIV chromatin should be preferred in vitro targets for the MGBDs. These results show that the MGBDs preferentially disrupt HIV-1 chromatin in vitro and in vivo and raise the possibility that non-toxic derivatives of certain MGBD might serve as a novel class of anti-HIV agents.3

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Section: Dicussionmentioning

confidence: 99%

Section: Dicussionmentioning

confidence: 99%

Section: Dicussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

HIV chromatin is a preferred target for drugs that bind in the DNA minor groove

Little

Schäfer

Anderson³

2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Accordingly, minor groove binders (MGBs) have previously been used to modulate DNAse I-dependent degradation of dsDNA, and are commonly used in footprinting assays [37][38] . Three major classes of canonical MGBs have been described: diamidines, benzimidazoles, and pyrrole-imidazole polyamides 39 . Extensive medicinal chemistry efforts have resulted in to the development of FDA-approved experimental drugs or clinical candidates for the treatment of both infectious diseases and cancer, with inhibition of replication being the primary mode of action (NCT 03824795 is an ongoing phase II clinical trials) [40][41] .…”

Section: Introductionmentioning

confidence: 99%

Controlling wireframe DNA origami nuclease degradation with minor groove binders

Wamhoff

Huang

Read

et al. 2020

Preprint

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Virus-like DNA nanoparticles have emerged as promising vaccine and gene delivery platforms due to their programmable nature that offers independent control over size, shape, and functionalization. However, as biodegradable materials, their utility for specific therapeutic indications depends on their structural integrity during biodistribution to efficiently target cells, tissues, or organs. Here, we explore reversible minor groove binders to control the degradation half-lives of wireframe DNA origami. Bare, two-helix DNA nanoparticles were found to be stable under typical cell culture conditions in presence of bovine serum, yet they remain susceptible to endonucleases, specifically DNAse I. Moreover, they degrade rapidly in mouse serum, suggesting species-specific degradation. Blocking minor groove accessibility with diamidines resulted in substantial protection against endonucleases, specifically DNAse-I. This strategy was found to be compatible with both varying wireframe DNA origami architectures and functionalization with protein antigens. Our stabilization strategy offers distinct physicochemical properties compared with established cationic polymer-based methods, with synergistic therapeutic potential for minor groove binder delivery for infectious diseases and cancer. MethodsMethods are described in the Supporting Information.

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DNA‐Triggered Enhancement of Singlet Oxygen Production by Pyridinium Alkynylanthracenes

Fudickar

Bauch

Ihmels

et al. 2021

Chemistry A European J

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There is an ongoing interest in 1O2 sensitizers, whose activity is selectively controlled by their interaction with DNA. To this end, we synthesized three isomeric pyridinium alkynylanthracenes 2 o–p and a water‐soluble trapping reagent for 1O2. In water and in the absence of DNA, these dyes show a poor efficiency to sensitize the photooxygenation of the trapping reagent as they decompose due to electron transfer processes. In contrast, in the presence of DNA 1O2 is generated from the excited DNA‐bound ligand. The interactions of 2 o–p with DNA were investigated by thermal DNA melting studies, UV/vis and fluorescence spectroscopy, and linear and circular dichroism spectroscopy. Our studies revealed an intercalative binding with an orientation of the long pyridyl‐alkynyl axis parallel to the main axis of the DNA base pairs. In the presence of poly(dA : dT), all three isomers show an enhanced formation of singlet oxygen, as indicated by the reaction of the latter with the trapping reagent. With green light irradiation of isomer 2 o in poly(dA : dT), the conversion rate of the trapping reagent is enhanced by a factor >10. The formation of 1O2 was confirmed by control experiments under anaerobic conditions, in deuterated solvents, or by addition of 1O2 quenchers. When bound to poly(dG : dC), the opposite effect was observed only for isomers 2 o and 2 m, namely the trapping reagent reacted significantly slower. Overall, we showed that pyridinium alkynylanthracenes are very useful intercalators, that exhibit an enhanced photochemical 1O2 generation in the DNA‐bound state.

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Recent developments in compounds acting in the DNA minor groove

Abstract: DNA minor groove is the target: the small molecules' attack.

Cited by 65 publications

References 88 publications

HIV chromatin is a preferred target for drugs that bind in the DNA minor groove

HIV chromatin is a preferred target for drugs that bind in the DNA minor groove

Controlling wireframe DNA origami nuclease degradation with minor groove binders

DNA‐Triggered Enhancement of Singlet Oxygen Production by Pyridinium Alkynylanthracenes

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