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Differential effects of the putative GBF1 inhibitors Golgicide A and AG1478 on enterovirus replication

Lonneke van der Linden1, Hilde M van der Schaar, Kjerstin H W Lanke

  • 1Department of Medical Microbiology, Nijmegen Centre for Molecular Life Sciences and Nijmegen Institute for Infection, Inflammation and Immunity, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.

Journal of Virology
|May 28, 2010
PubMed

Insights

Golgicide A (GCA) inhibits enterovirus replication by targeting Golgi-specific BFA resistance factor 1 (GBF1). Unlike AG1478, GCA suppresses viral RNA replication, making it a potential tool for studying enteroviruses.

Area of Science:

  • Virology
  • Cell Biology
  • Drug Discovery

Background:

  • Enteroviruses, including poliovirus and coxsackievirus, are significant human pathogens.
  • Brefeldin A (BFA) inhibits enterovirus replication by targeting Golgi-specific BFA resistance factor 1 (GBF1), crucial for secretory pathway function.
  • GBF1 regulates Arf1 GTP exchange, influencing coatomer protein complex I (COP-I) recruitment for vesicle transport.

Purpose of the Study:

  • To investigate the effects of novel GBF1 inhibitors, AG1478 and Golgicide A (GCA), on secretory pathway function and enterovirus replication.
  • To elucidate the molecular mechanisms by which AG1478 and GCA affect GBF1 and viral replication.

Main Methods:

  • Treatment of cells with AG1478 and GCA to assess effects on Golgi vesicles, Arf1, and COP-I localization.
  • Overexpression of Arf1 and GBF1 to determine rescue effects on drug-induced inhibition.
  • Analysis of coxsackievirus B3 (CVB3) replication and RNA synthesis using time-of-addition studies and subgenomic replicons.

Main Results:

  • Both AG1478 and GCA induced Golgi vesicle fragmentation and dissociation of Arf1/COP-I from Golgi membranes.
  • GCA, but not AG1478, significantly reduced CVB3 and other enterovirus replication.
  • GCA suppressed CVB3 RNA replication, an effect reversible by GBF1 overexpression, indicating direct targeting of GBF1.

Conclusions:

  • Golgicide A (GCA) directly inhibits enterovirus RNA replication by targeting GBF1, unlike AG1478.
  • AG1478 and GCA represent valuable pharmacological tools for dissecting enterovirus replication mechanisms.

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