tetano
Editor, Senior Moderator
Front Immunol
. 2025 Sep 22:16:1631721.
doi: 10.3389/fimmu.2025.1631721. eCollection 2025. Antiviral and immunomodulatory effect of zapnometinib in animal models and hospitalized COVID-19 patients
Yvonne Füll[SUP] 1 2 [/SUP], Lara M Schüssele[SUP] 1 2 [/SUP], Hazem Hamza[SUP] 1 2 3 [/SUP], Helen Hoffmann[SUP] 1 2 [/SUP], Martin Bauer[SUP] 2 [/SUP], Stephan Stenglein[SUP] 2 [/SUP], Oliver Pötz[SUP] 4 [/SUP], Andreas Steinhilber[SUP] 4 [/SUP], Viktoria Anselm[SUP] 4 [/SUP], Mark W Delany[SUP] 5 [/SUP], Judith M A Van den Brand[SUP] 5 [/SUP], Geert Van Amerongen[SUP] 6 [/SUP], Leon De Waal[SUP] 6 [/SUP], Stephan Pleschka[SUP] 7 [/SUP], Stephan Ludwig[SUP] 8 [/SUP], Oliver Planz[SUP] 1 [/SUP]
Affiliations
Introduction: In severe COVID-19, direct-acting antiviral drugs were not effective in hyperinflammatory stages and steroid treatment may weaken host immunity. The MEK inhibitor zapnometinib, as a host-targeting drug, has demonstrated promising efficacy against severe acute viral infections. Proof-of-concept for the innovative approach was presented in a clinical Phase 2 trial with hospitalized COVID-19 patients.
Methods: The antiviral and immunomodulatory potential of zapnometinib was investigated in samples obtained from COVID-19 patients enrolled in a Phase 2 clinical trial (RESPIRE), as well as in a SARS-CoV-2 Syrian hamster model, an acute lung injury mouse model, and in cell culture. The antiviral activity of zapnometinib was assessed using viral load reduction assays and RT-qPCR. Cytokines and chemokines were analyzed via ELISA and RT-qPCR. Alterations in T and B cells from COVID-19 patients were analyzed using flow cytometry. Biomarker analysis in hamster serum was conducted to monitor potential toxic effects.
Results: Zapnometinib reduced SARS-CoV-2 viral load in hospitalized COVID-19 patients, in the hamster model and in various highly pathogenic coronaviruses in vitro. Pro-inflammatory cytokines and chemokines decreased in COVID-19 patients, in a lung injury mouse model, and in vitro in primary human blood cells treated with zapnometinib. In the hamster model, zapnometinib alleviated SARS-CoV-2-mediated lung pathology. In patients with COVID-19, zapnometinib increased T and plasma B cells.
Conclusion: Unlike direct-acting antivirals, zapnometinib's dual effect highlights its therapeutic potential in the treatment of severe acute viral infections, with favorable antiviral and immunomodulatory properties.
Keywords: COVID-19; MEK inhibitor; broad-spectrum antiviral; drug development; host targeting agent; immunomodulation; zapnometinib.
. 2025 Sep 22:16:1631721.
doi: 10.3389/fimmu.2025.1631721. eCollection 2025. Antiviral and immunomodulatory effect of zapnometinib in animal models and hospitalized COVID-19 patients
Yvonne Füll[SUP] 1 2 [/SUP], Lara M Schüssele[SUP] 1 2 [/SUP], Hazem Hamza[SUP] 1 2 3 [/SUP], Helen Hoffmann[SUP] 1 2 [/SUP], Martin Bauer[SUP] 2 [/SUP], Stephan Stenglein[SUP] 2 [/SUP], Oliver Pötz[SUP] 4 [/SUP], Andreas Steinhilber[SUP] 4 [/SUP], Viktoria Anselm[SUP] 4 [/SUP], Mark W Delany[SUP] 5 [/SUP], Judith M A Van den Brand[SUP] 5 [/SUP], Geert Van Amerongen[SUP] 6 [/SUP], Leon De Waal[SUP] 6 [/SUP], Stephan Pleschka[SUP] 7 [/SUP], Stephan Ludwig[SUP] 8 [/SUP], Oliver Planz[SUP] 1 [/SUP]
Affiliations
- PMID: 41058679
- PMCID: PMC12498288
- DOI: 10.3389/fimmu.2025.1631721
Introduction: In severe COVID-19, direct-acting antiviral drugs were not effective in hyperinflammatory stages and steroid treatment may weaken host immunity. The MEK inhibitor zapnometinib, as a host-targeting drug, has demonstrated promising efficacy against severe acute viral infections. Proof-of-concept for the innovative approach was presented in a clinical Phase 2 trial with hospitalized COVID-19 patients.
Methods: The antiviral and immunomodulatory potential of zapnometinib was investigated in samples obtained from COVID-19 patients enrolled in a Phase 2 clinical trial (RESPIRE), as well as in a SARS-CoV-2 Syrian hamster model, an acute lung injury mouse model, and in cell culture. The antiviral activity of zapnometinib was assessed using viral load reduction assays and RT-qPCR. Cytokines and chemokines were analyzed via ELISA and RT-qPCR. Alterations in T and B cells from COVID-19 patients were analyzed using flow cytometry. Biomarker analysis in hamster serum was conducted to monitor potential toxic effects.
Results: Zapnometinib reduced SARS-CoV-2 viral load in hospitalized COVID-19 patients, in the hamster model and in various highly pathogenic coronaviruses in vitro. Pro-inflammatory cytokines and chemokines decreased in COVID-19 patients, in a lung injury mouse model, and in vitro in primary human blood cells treated with zapnometinib. In the hamster model, zapnometinib alleviated SARS-CoV-2-mediated lung pathology. In patients with COVID-19, zapnometinib increased T and plasma B cells.
Conclusion: Unlike direct-acting antivirals, zapnometinib's dual effect highlights its therapeutic potential in the treatment of severe acute viral infections, with favorable antiviral and immunomodulatory properties.
Keywords: COVID-19; MEK inhibitor; broad-spectrum antiviral; drug development; host targeting agent; immunomodulation; zapnometinib.