Glimepiride increases cGAS-STING sensitivity to double-stranded DNA and improves antiviral immunity without excessive inflammation

Current small-molecule immune activators often lack specificity and cause toxicity, underscoring the need for safer host-directed antivirals. We found that glimepiride (GM), an FDA-approved sulfonylurea, directly bound and potentiated human cGAS, elevating cGAMP and engaging STING-TBK1-IFN-I signaling. In PBMCs, GM upregulated IFN-I programs, whereas in primary CD14+ monocytes it dampened LPS-driven inflammatory gene expression. Mechanistically, GM directly bound cGAS and acted independently of the cGAS DNA-binding surface and without reliance on exogenous cytosolic DNA. By allosterically sensitizing the catalytic core and lowering the activation threshold, basal mtDNA was sufficient to drive cGAMP production. In mice, GM elicited systemic IFN-I, lowered viral loads, and improved survival after RNA and DNA virus challenge, while mitigating inflammation and mortality in LPS-induced sepsis, with good tolerability. These findings define pharmacologic cGAS potentiation by GM as a practical host-directed antiviral approach and support repurposing GM as an orally available broad-spectrum antiviral with anti-inflammatory benefit.