In vivo antiviral efficacy and immune dampening effect of zapnometinib emphasize a dual therapeutic potential against COVID-19

Abstract

Coronaviruses, in particular the current pandemic strains of SARS-CoV-2, represent an ever-evolving threat to human life. Currently available antiviral drugs are not suitable for severely infected patients in later hyperinflammatory stages of the disease. New therapeutics that inhibit virus propagation and target inflammation would be ideal. We demonstrate that the host targeted MEK inhibitor zapnometinib displays such a dual effect. The drug efficiently reduced virus titers of different SARS-CoV-2 variants and other highly pathogenic human coronaviruses such as SARS-CoV-1 and MERS-CoV in vitro. In a Syrian hamster infection model, zapnometinib reduced SARS-CoV-2 viral load and alleviated lung pathology. Drug safety biomarkers, body weight change and clinical observations, indicated that zapnometinib was well tolerated and showed no toxicity. Moreover, the immune dampening effect could be confirmed in an acute lung injury mouse model and in vitro experiments in primary human blood cells that demonstrated the reduction of disease related cytokines and chemokines. Thus, in contrast to direct-acting antivirals, zapnometinib displays a dual therapeutic effect highlighting its potential in the treatment of severe COVID-19 and other acute viral infections leading to hyperinflammation.