2. Academic Validation
  3. Antiviral efficacy against influenza virus and pharmacokinetic analysis of a novel MEK-inhibitor, ATR-002, in cell culture and in the mouse model

Antiviral efficacy against influenza virus and pharmacokinetic analysis of a novel MEK-inhibitor, ATR-002, in cell culture and in the mouse model

  • Antiviral Res. 2020 Jun;178:104806. doi: 10.1016/j.antiviral.2020.104806.
Martin Laure 1,  Hazem Hamza 2,  Julia Koch-Heier 1,  Martin Quernheim 3,  Christin Müller 4,  Andre Schreiber 5,  Gerhard Müller 6,  Stephan Pleschka 4,  Stephan Ludwig 5,  Oliver Planz 7
Affiliations

Affiliations

  • 1 Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University, Tübingen, Germany; Atriva Therapeutics GmbH, Christophstr. 32, 72072, Tübingen, Germany.
  • 2 Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University, Tübingen, Germany; Atriva Therapeutics GmbH, Christophstr. 32, 72072, Tübingen, Germany; Virology Laboratory, Environmental Research Division, National Research Centre, Cairo, Egypt.
  • 3 Chemcon GmbH, Engesserstr. 4B, 79108, Freiburg I. Brsg., Germany.
  • 4 Institute of Medical Virology, Justus Liebig University, Giessen, Germany.
  • 5 Institute of Virology, Westfaelische Wilhelms-University, Muenster, Germany.
  • 6 Gotham Therapeutics, New York, USA.
  • 7 Interfaculty Institute for Cell Biology, Department of Immunology, Eberhard Karls University, Tübingen, Germany; Atriva Therapeutics GmbH, Christophstr. 32, 72072, Tübingen, Germany. Electronic address: oliver.planz@uni-tuebingen.de.
PMID: 32304723 DOI: 10.1016/j.antiviral.2020.104806
Abstract

Antiviral therapies against influenza are required, especially for high-risk patients, severe influenza and in case of highly pathogenic Influenza Virus (IV) strains. However, currently, licensed drugs that target the virus directly are not very effective and often lead to the development of resistant IV variants. This may be overcome by targeting host cell factors that are required for IV propagation. IV induces a variety of host cell signaling cascades, such as the Raf/MEK/ERK kinase pathway. The activation of this pathway is necessary for IV propagation. MEK-inhibitors block the activation of the pathway on the bottleneck of the signaling cascade leading to impaired virus propagation. In the present study, we aimed to compare the Antiviral potency and bioavailability of the MEK-inhibitor CI-1040 versus its major active metabolite ATR-002, in vitro as well as in the mouse model. In Cell Culture assays, an approximately 10-fold higher concentration of ATR-002 is required to generate the same Antiviral activity as for CI-1040. Interestingly, we observed that considerably lower concentrations of ATR-002 were required to achieve a reduction of the viral load in vivo. Pharmacokinetic studies with ATR-002 and CI-1040 in mice have found the Cmax and AUC to be far higher for ATR-002 than for CI-1040. Our results thereby demonstrate the in vivo superiority of the active metabolite ATR-002 over CI-1040 as an Antiviral agent despite its weaker cell membrane permeability. Therefore, ATR-002 is an attractive candidate for development as an efficient Antiviral agent, especially given the fact that a treatment based on cellular pathway inhibition would be far less likely to lead to viral drug resistance.

Keywords

Antiviral; Bioavailability; Influenza virus; MEK-Inhibitor; Pharmacokinetic.

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