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The MEK1/2 Inhibitor ATR-002 (Zapnometinib) Synergistically Potentiates the Antiviral Effect of Direct-Acting

André Schreiber1, Benjamin Ambrosy1, Oliver Planz2

  • 1Institute of Virology (IVM), Centre for Molecular Biology of Inflammation, University of Muenster, 48149 Muenster, Germany.

Pharmaceutics
|September 23, 2022
PubMed

Insights

The MEK1/2 inhibitor ATR-002 potentiates direct-acting antivirals (DAAs) against SARS-CoV-2. Combining ATR-002 with DAAs like Molnupiravir or Paxlovid shows synergistic effects, reducing effective drug concentrations.

Area of Science:

  • Virology
  • Pharmacology
  • Infectious Diseases

Background:

  • COVID-19 remains a global health challenge requiring effective antiviral treatments.
  • Combination therapy offers a potential strategy to enhance antiviral efficacy and overcome resistance.
  • Host-targeted antivirals, like MEK1/2 inhibitors, are being explored for their synergistic potential.

Purpose of the Study:

  • To investigate the synergistic effect of ATR-002 (zapnometinib), a MEK1/2 inhibitor, in combination with direct-acting antivirals (DAAs) against SARS-CoV-2.
  • To evaluate the potentiation of antiviral activity by ATR-002 when combined with nucleoside analogs and protease inhibitors.
  • To assess the safety and efficacy of these combinations in a cellular model of SARS-CoV-2 infection.

Main Methods:

  • Calu-3 cells were infected with SARS-CoV-2 and treated with ATR-002 in combination with various DAAs.
  • Tested DAAs included nucleoside inhibitors (Molnupiravir, Remdesivir) and protease inhibitors (Nirmatrelvir/Ritonavir - Paxlovid).
  • Synergistic effects were quantified using four different reference models across a range of drug concentrations.

Main Results:

  • All tested combinations of ATR-002 with DAAs demonstrated synergistic antiviral effects against SARS-CoV-2 replication.
  • Synergy was observed across a concentration range where ATR-002 and the DAAs were well-tolerated by Calu-3 cells.
  • The combination therapy allowed for a reduction in the effective concentrations of individual antiviral drugs.

Conclusions:

  • ATR-002 exhibits significant potential for synergistic activity when combined with existing direct-acting antivirals against SARS-CoV-2.
  • This combination approach may enable lower effective doses of antivirals, potentially reducing side effects and improving treatment outcomes.
  • Further research into ATR-002 combination therapy could lead to more effective COVID-19 treatment strategies.
Keywords:
ATR-002COVID-19MEK1/2 inhibitorMolnupiravirNirmatrelvirPaxlovidRemdesivirRitonavirSARS-CoV-2antiviral drugdrug synergy

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