The binding mode of the DNA bisintercalator luzopeptin investigated using atomic force microscopy

Berge, Torunn; Haken, E Lucy; Waring, Michael J.; Henderson, Ronald W.

doi:10.1016/s1047-8477(03)00015-7

Cited by 20 publications

(16 citation statements)

References 19 publications

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“…137 Van der Waals interactions between the methyl groups of luzopeptin and the minor groove surface have also been identified. 133 All the base-pairs retain a Watson-Crick alignment, with no evidence of Hoogsteen basepairing.…”

Section: Biological Activity Of the Luzopeptinsmentioning

confidence: 98%

Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies

et al. 2007

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Echinomycin is the prototypical bisintercalator, a molecule that binds to DNA by inserting two planar chromophores between the base-pairs of duplex DNA, placing its cyclic depsipeptide backbone in the minor groove. As such, it has been the focus of an extensive number of investigations into its biological activity, nucleic acid binding and, to some extent, its structure-activity relationships. However, echinomycin is also the parent member of an extended family of natural products that interact with DNA by a similar mechanism of bisintercalation. The structural variety in these compounds leads to changes in sequence selectivity and and biological activity, particularly as anti-tumour and anti-viral agents. One of the more recently identified marine natural products that is moving close to clinical development is thiocoraline, and it therefore seems timely to review the various bisintercalator natural products.

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Section: Biological Activity Of the Luzopeptinsmentioning

confidence: 98%

Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies

et al. 2007

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“…At this respect, it is noteworthy to mention that experiments using just the sandramycin peptide scaffold have demonstrated a high binding affinity to DNA minor groove [78]. Luzopeptin A and quinoxapeptin A (Major scaffold members), show also a preference for 5′-AT sequences [93,94,95]. Surprisingly, some Major scaffold members have been described also to carry out a bisintercalation between two different DNA helixes (each chromophore binding to a different DNA minor groove) as well as the canonical intramolecular DNA bisintercalation.…”

Section: Bioactivity Of Bisintercalator Compoundsmentioning

confidence: 99%

Biosynthetic Modularity Rules in the Bisintercalator Family of Antitumor Compounds

et al. 2014

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Diverse actinomycetes produce a family of structurally and biosynthetically related non-ribosomal peptide compounds which belong to the chromodepsipeptide family. These compounds act as bisintercalators into the DNA helix. They give rise to antitumor, antiparasitic, antibacterial and antiviral bioactivities. These compounds show a high degree of conserved modularity (chromophores, number and type of amino acids). This modularity and their high sequence similarities at the genetic level imply a common biosynthetic origin for these pathways. Here, we describe insights about rules governing this modular biosynthesis, taking advantage of the fact that nowadays five of these gene clusters have been made public (thiocoraline, triostin, SW-163 and echinomycin/quinomycin). This modularity has potential application for designing and producing novel genetic engineered derivatives, as well as for developing new chemical synthesis strategies. These would facilitate their clinical development.

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“…One of the signature effects observed in DNA intercalators is that they increase the contour length of the DNA due to the stacking of the intercalating agent between two DNA base pairs (33, 51, 52). The intercalation of PT-ACRAMTU in DNA linearly increases the contour length by up to 0.6 nm/drug molecule before reaching a saturation phase at 15 % PT-ACRAMTU-to-DNA base pair ratio (Fig.…”

Section: Discussionmentioning

confidence: 99%

PT-ACRAMTU, A Platinum–Acridine Anticancer Agent, Lengthens and Aggregates, but does not Stiffen or Soften DNA

Dutta

Snyder

Rosile

et al. 2013

Cell Biochem Biophys

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We used atomic force microscopy (AFM) to study the dose-dependent change in conformational and mechanical properties of DNA treated with PT-ACRAMTU ([PtCl(en)(ACRAMTU-S)](NO3)2, (en = ethane-1,2-diamine, ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea. PT-ACRAMTU is the parent drug of a family of nonclassical platinum-based agents that show potent activity in non-small cell lung cancer in vitro and in vivo. Its acridine moiety intercalates between DNA bases, while the platinum group forms monoadducts with DNA bases. AFM images show that PT-ACRAMTU causes some DNA looping and aggregation at drug-to-base pair ratio (rb) of 0.1 and higher. Very significant lengthening of the DNA was observed with increasing doses of PT-ACRAMTU, and reached saturation at an rb of 0.15. At rb of 0.1, lengthening was 0.6 nm per drug molecule, which is more than one fully stretched base pair stack can accommodate, indicating that ACRAMTU also disturbs the stacking of neighboring base pair stacks. Analysis of the AFM images based on the worm-like chain (WLC) model showed that PT-ACRAMTU did not change the flexibility of (non-aggregated) DNA, despite the extreme lengthening. The persistence length of untreated DNA and DNA treated with PT-ACRAMTU was in the range of 49 to 65 nm. Potential consequences of the perturbations caused by this agent for the recognition and processing of the DNA adducts it forms are discussed.

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The binding mode of the DNA bisintercalator luzopeptin investigated using atomic force microscopy

Cited by 20 publications

References 19 publications

Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies

Bisintercalator natural products with potential therapeutic applications: isolation, structure determination, synthetic and biological studies

Biosynthetic Modularity Rules in the Bisintercalator Family of Antitumor Compounds

PT-ACRAMTU, A Platinum–Acridine Anticancer Agent, Lengthens and Aggregates, but does not Stiffen or Soften DNA

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