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Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication

Cynthia Mathew1, Sharon Tamir2, Ralph A Tripp3

  • 1Centre for Research in Therapeutic Solutions, Faculty of Science and Technology, University of Canberra, Canberra, ACT 2617, Australia.

Scientific Reports
|September 29, 2021
PubMed

Insights

Selective Inhibitor of Nuclear Export (SINE) compounds reduced respiratory syncytial virus (RSV) replication by inhibiting exportin-1 (XPO1). This reversible inhibition disrupted viral assembly and replication pathways, offering a potential therapeutic strategy.

Area of Science:

  • Virology
  • Molecular Biology
  • Pharmacology

Background:

  • Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease, particularly in vulnerable populations.
  • Current RSV therapies are limited, and effective vaccines are unavailable.
  • RSV assembly relies on the nuclear export of its Matrix (M) protein via exportin-1 (XPO1).

Purpose of the Study:

  • To evaluate the anti-RSV efficacy of Selective Inhibitor of Nuclear Export (SINE) compounds KPT-335 and KPT-185.
  • To investigate the mechanism by which SINE compounds affect RSV replication.

Main Methods:

  • Treatment of human respiratory epithelial cell cultures with SINE compounds.
  • Assessment of RSV titre, replication, XPO1 expression, M protein localization, and cell cycle progression.
  • Evaluation of the reversibility of SINE compound effects.

Main Results:

  • SINE compounds significantly reduced RSV titre in cell culture.
  • Treatment led to decreased RSV replication and XPO1 expression within 24 hours.
  • M protein was partially retained in the nucleus, and cell cycle progression was delayed.
  • The antiviral effects were reversible upon compound removal.

Conclusions:

  • Reversible inhibition of XPO1 by SINE compounds effectively disrupts RSV replication.
  • This disruption occurs by interfering with downstream pathways regulated by XPO1.
  • SINE compounds represent a promising therapeutic avenue for RSV infections.

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