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Novel and specific inhibitors of a poxvirus type I topoisomerase

Alexis Bond1, Zachary Reichert, James T Stivers

  • 1Department of Pharmacology and Molecular Sciences, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205-2185, USA.

Molecular Pharmacology
|November 4, 2005
PubMed

Insights

Researchers identified novel small-molecule inhibitors targeting vaccinia DNA topoisomerase (vTopo), crucial for viral replication. These compounds are highly specific for vTopo, showing no inhibition against the human enzyme, offering potential therapeutic avenues.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Virology

Background:

  • Vaccinia DNA topoisomerase (vTopo) is essential for poxvirus replication and shares similarities with human topoisomerase I (hTopo).
  • Despite structural similarities, vTopo and hTopo exhibit distinct pharmacological profiles, presenting an opportunity for targeted drug development.

Purpose of the Study:

  • To develop and implement a high-throughput screening (HTS) assay for identifying vTopo inhibitors.
  • To characterize novel small-molecule inhibitors that selectively target vTopo over hTopo.

Main Methods:

  • A high-throughput screen of a 1990-member small-molecule library was conducted against vTopo.
  • Inhibitory activity was assessed by measuring DNA supercoil relaxation.
  • Potent inhibitors were further characterized using various biochemical assays to determine their mechanism of action and specificity.

Main Results:

  • The HTS identified 21 compounds with IC(90) values below 10 muM, with 19 inhibiting vTopo DNA supercoil relaxation.
  • Four novel, potent vTopo inhibitors were characterized, demonstrating nanomolar efficacy.
  • These inhibitors exhibited high specificity for vTopo, with no observed inhibition of hTopo even at significantly higher concentrations (500- to 2000-fold).

Conclusions:

  • Novel, highly specific vTopo inhibitors have been discovered using a new HTS assay.
  • These compounds represent promising leads for antiviral therapies targeting poxviruses.
  • The study highlights the distinct pharmacological properties of vTopo and its susceptibility to diverse small-molecule inhibitors.

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