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Inhibition of large T antigen ATPase activity as a potential strategy to develop anti-polyomavirus JC drugs

Parmjeet Randhawa1, G Zeng1, M Bueno1

  • 1University of Pittsburgh, Pittsburgh, PA, USA.

Antiviral Research
|December 3, 2014
PubMed
Abstract

Insights

Researchers identified five compounds that inhibit polyomavirus JC (JCV) large T antigen (LTA) ATPase activity, showing potential for antiviral drug development. Further optimization is needed to reduce toxicity and enhance efficacy for clinical use.

Area of Science:

  • Virology
  • Drug Discovery
  • Biochemistry

Background:

  • Polyomavirus JC (JCV) large T antigen (LTA) is crucial for viral replication.
  • LTA's helicase and ATPase activity, essential for viral replication, presents a potential drug target.
  • Developing drugs targeting JCV LTA could offer new antiviral strategies.

Purpose of the Study:

  • To evaluate JCV LTA as a drug development target.
  • To screen for compounds inhibiting JCV LTA ATPase activity.
  • To assess the antiviral and toxicological profiles of identified compounds.

Main Methods:

  • Recombinant JCV LTA was expressed and its ATPase activity measured.
  • A high-throughput screen of 75,000 drug-like compounds was performed.
  • Antiviral activity was assessed using immunofluorescence and real-time PCR assays.

Main Results:

  • Five compounds demonstrated non-competitive inhibition of LTA ATPase activity (EC50 ≤ 15 μM).
  • These compounds exhibited modest antiviral activity against JCV in cell-based assays.
  • Compounds showed low cytotoxicity, but two inhibited cell proliferation at higher concentrations.

Conclusions:

  • JCV LTA ATPase is a viable target for antiviral drug discovery.
  • Further screening and chemical optimization are required to develop safe and effective clinical compounds.
  • Assessing metabolic and cell proliferation assays is crucial for evaluating compound toxicity.
Keywords:
ATPaseDrugsLarge T antigenPolyomavirus JC

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