MEK inhibitors as novel host-targeted antivirals with a dual-benefit mode of action against hyperinflammatory respiratory viral diseases

Abstract

Acute hyperinflammatory virus infections, such as influenza or coronavirus disease-19, are still a major health burden worldwide. In these diseases, a massive overproduction of pro-inflammatory cytokines and chemokines (cytokine storm syndrome) determine the severity of the disease, especially in late stages. Direct-acting antivirals against these pathogens have to be administered very early after infection to be effective and may induce viral resistance. Here, we summarize data on a host-targeted strategy using inhibitors of the cellular Raf/MEK/ERK kinase cascade that not only block replication of different RNA viruses but also suppress the hyperinflammatory cytokine response upon infection. In the first phase-II clinical trial of that approach, the MEK inhibitor Zapnometinib shows evidence of clinical benefit.

Figure 1

Infection of cells with influenza virus, SARS-CoV-2 or RSV, leads to activation of the Raf/MEK/ERK pathway via different pathogen-associated molecular patterns such as vRNA accumulation or membrane accumulation of HA (IAV/IVB). Viruses have acquired the capability to exploit cellular signaling via the core kinases Raf, MEK, and ERK to support different steps in the virus life cycle, such as vRNP export (IAV/IBV), F-protein translocation (RSV), or entry (SARS-CoV-2). Infection also leads to induction of proinflammatory cytokines (presumably by regulation of the transcription factor NF-kB) and the type-I antiviral IFN response. Inhibition of Raf/MEK/ERK signaling by MEK inhibitors such as Zapnometinib impairs virus replication and also dampens proinflammatory cytokine expression, while the activation of STAT1 and the antiviral type-I IFN response is not significantly affected (effects of MEK inhibition shown in red). MEK inhibition also affects replication of other viruses such as hantaviruses or BoDV, however, the mechanisms of pathway activation and the step in the virus life cycle that is affected are less clear.