Targeting DNA Topoisomerases in Therapeutics

DNA topoisomerases are essential enzymes that regulate the topological state of genomic DNA by introducing transient strand breaks to relieve supercoiling and entanglements generated during replication, transcription and chromosome segregation. Two major classes, type I and type II, differ in their mechanism of action and in the number of strands they cleave. Therapeutic exploitation of these enzymes centres on two principal modalities: poisons that stabilise the covalent cleavage complex, inducing persistent DNA breaks and cell death, and catalytic inhibitors that prevent strand cleavage or religation without trapping the enzyme on DNA. Clinically, topoisomerase II poisons such as etoposide and anthracyclines remain mainstays of anticancer regimens, whereas inhibitors of bacterial gyrase and topoisomerase IV underpin fluoroquinolone and novel antibacterial therapies. Ongoing challenges include achieving isoform selectivity to limit off-target toxicity, overcoming drug resistance through structural insights, and harnessing natural product scaffolds and dual-target approaches to expand the therapeutic repertoire. Advances in structural biology and single-molecule techniques are now informing rational drug design, guiding the development of next-generation agents with improved efficacy and safety profiles.

Research from Nature Portfolio

Recent studies have elucidated how chemotherapeutic agents modulate topoisomerase dynamics at the single-molecule level. One investigation revealed that etoposide not only stabilises the cleavage complex but also promotes the trapping of DNA loops by topoisomerase II, compacting and restraining DNA topology after ATP hydrolysis but before strand ejection. This mechanistic insight explains differential compaction and barrier-forming properties of human and yeast isoforms under drug treatment. In parallel, high-resolution cryo-electron microscopy of the full Escherichia coli DNA gyrase nucleoprotein complex has provided the first atomic-level view of antibiotic binding within the cleavage core, capturing distinct conformational states and mapping the binding site of a novel gyrase inhibitor. These structural snapshots supply a foundation for structure-guided design of isoform-specific and resistance-evading topoisomerase-targeting drugs.

Targeting DNA Topoisomerases in Therapeutics publication trend

The graph below shows the total number of articles in targeting dna topoisomerases in therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

DNA topoisomerase: Enzymes that modulate the topological state of DNA by inducing transient breaks to enable strand passage and relieve torsional strain.

DNA supercoiling: Over- or under-winding of the DNA double helix that arises during replication and transcription.

Cleavage complex: An intermediate in which a topoisomerase is covalently bound to a cleaved DNA strand, susceptible to drug stabilisation.

Topoisomerase poison: A compound that stabilises the cleavage complex, leading to persistent DNA breaks and cytotoxicity.

Catalytic inhibitor: A molecule that prevents enzyme-mediated strand cleavage or religation without stabilising DNA breaks.

References

1. Using energy to go downhill—a genoprotective role for ATPase activity in DNA topoisomerase II. Nucleic Acids Research (2023).
2. Etoposide promotes DNA loop trapping and barrier formation by topoisomerase II. Nature Chemical Biology (2023).
3. Flavonoids and their derivatives as DNA topoisomerase inhibitors with anti-cancer activity in various cell models: Exploring a novel mode of action. Pharmacological Research (2024).
4. Cryo-EM structure of the complete E. coli DNA gyrase nucleoprotein complex. Nature Communications (2019).