GHRH antagonist MIA-602 inhibits SARS-CoV-2 spike protein and LPS-induced inflammation in macrophages and PBMCs

Severe COVID-19 is characterized by an excessive inflammatory response and macrophage hyperactivation, often leading to alveolar epithelial injury and acute respiratory distress syndrome (ARDS). Recent research highlights that SARS-CoV-2 spike (S) protein synergizes with bacterial lipopolysaccharide (LPS) to amplify inflammatory responses. While Growth Hormone-Releasing Hormone (GHRH) acts as a growth factor, its antagonists, like MIA-602, have demonstrated potent antitumor and anti-inflammatory activities in various cell types. However, the specific anti-inflammatory role of GHRH antagonists in the context of COVID-19-related inflammation remained unexplored.

Researchers investigated the anti-inflammatory effects of MIA-602 in human THP-1-derived macrophages and peripheral blood mononuclear cells (PBMCs). Cells were stimulated with a combination of SARS-CoV-2 S protein and LPS to induce an inflammatory state. The presence of GHRH receptor and its SV1 splice variant was confirmed in both cell types using Western blot and immunofluorescence. The study then assessed the impact of MIA-602 on inflammatory cytokine and chemokine expression and secretion, as well as the activation of key inflammatory signaling pathways, under these stimulated conditions.

The study confirmed the presence of GHRH receptor and its SV1 splice variant in both THP-1 cells and PBMCs. Exposure of THP-1 cells to the S protein and LPS combination significantly increased the mRNA levels and protein secretion of pro-inflammatory cytokines TNF-α and IL-1β, alongside elevated IL-8 and MCP-1 gene expression. This inflammatory surge was effectively hampered by MIA-602. Similarly, MIA-602 hindered TNF-α and IL-1β secretion in PBMCs and reduced MCP-1 mRNA levels. Mechanistically, MIA-602 blunted the S protein and LPS-induced activation of several key inflammatory pathways, including NF-κB, MAPK/ERK, p38, and JNK.