MEK1/2 inhibitor ATR-002 reshapes host transcriptome and modulates immune regulatory genes in SARS-CoV-2 infection.

Introduction: SARS-CoV-2 portrays a public health threat because severe progression of infections can lead to hospitalization. Severity is often characterized by a systemic inflammatory response in later stages, along with disbalance in cytokine production, multi-organ failure, or acute respiratory distress syndrome (ARDS). As severe infections can be challenging due to limited treatment windows for direct-acting antivirals, host-targets, e.g., the Raf/MEK/ERK signaling cascade, came into focus. Specifically, MEK1/2 has been suggested as a target for antiviral and anti-inflammatory therapy. A recent phase II clinical trial showed the efficacy of the MEK1/2 inhibitor zapnometinib (ZMN/ATR-002) in hospitalized COVID-19 patients. The anti-inflammatory action of ATR-002 was only studied on some candidate cytokines. Methods: To generate a comprehensive overview of transcriptional effects on immune regulatory genes, we performed a transcriptome analysis of SARS-CoV-2-infected Calu-3 cells in the presence or absence of ATR-002. Results: Gene expression data revealed significant upregulation of innate immune-response-related genes, e.g., cytokines ( Discussion: With our analysis of transcriptional regulation after SARS-CoV-2 infection and the potential influence of ATR-002, we were able to identify ERK1/2-dependent gene expression and candidate genes (EGR1, IFNL1, and NLRP1), which could be involved in the regulation of innate immune-response-related processes.