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Tyrosyl-DNA phosphodiesterase inhibitors: Progress and potential

Sergey S Laev1, Nariman F Salakhutdinov2, Olga I Lavrik3

  • 1Vorozhtsov Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences, pr. akademika Lavrent'eva 9, Novosibirsk 630090, Russian Federation.

Bioorganic & Medicinal Chemistry
|October 1, 2016
PubMed

Insights

Tyrosyl-DNA phosphodiesterase inhibitors offer new therapeutic strategies. Inhibiting tyrosyl-DNA phosphodiesterase 1 can enhance topoisomerase I inhibitor efficacy, while blocking tyrosyl-DNA phosphodiesterase 2 may overcome resistance to topoisomerase II drugs.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • DNA topoisomerases are crucial for DNA replication and transcription.
  • Topoisomerase inhibitors function by enzyme poisoning.
  • Tyrosyl-DNA phosphodiesterases (TDPs) are DNA repair enzymes critical for resolving topoisomerase-DNA covalent complexes.

Purpose of the Study:

  • To explore the therapeutic potential of tyrosyl-DNA phosphodiesterase inhibitors.
  • To investigate TDP inhibitors as synergistic agents with topoisomerase inhibitors.
  • To examine TDP inhibitors for overcoming drug resistance in cancer therapy.

Main Methods:

  • Review of enzyme structures and mechanisms of action.
  • Analysis of therapeutic rationale for TDP inhibition.
  • Discussion of development strategies for TDP inhibitors.

Main Results:

  • Tyrosyl-DNA phosphodiesterase 1 inhibition potentiates topoisomerase I poisons.
  • Tyrosyl-DNA phosphodiesterase 2 inhibition can overcome resistance to topoisomerase II poisons.
  • TDP inhibitors show promise as anticancer and antiviral agents.

Conclusions:

  • Tyrosyl-DNA phosphodiesterase 1 and 2 inhibitors have significant therapeutic potential.
  • Targeting TDPs offers novel strategies for cancer and antiviral therapies.
  • Further development of TDP inhibitors may enhance existing chemotherapies.
Keywords:
CamptothecinDNA repairIndenoisoquinolinesTdp1Tdp1 inhibitorsTdp2Tdp2 inhibitorsTop1 inhibitorsTop2 inhibitorsTopoisomeraseTyrosyl-DNA phosphodiesterase

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