Ellipticine Derivatives as Toll-like Receptor 3 Inhibitor for Treating Acute Hepatitis

Abstract

Toll-like receptor 3 (TLR3) has been shown to influence various liver diseases. By screening a natural product molecular library, we discovered that Ellipticine exhibits moderate TLR3 inhibitory effects, with an IC₅₀ value of 5.66 ± 1.03 μM. Subsequent optimization of Ellipticine led to the development of the most potent compound, SMU-14a, which achieved an IC₅₀ of 0.18 ± 0.02 μM among all 31 derivatives. SMU-14a effectively inhibits IL-6 secretion in mouse peritoneal macrophages triggered by polyinosinic-polycytidylic acid (Poly I:C, a TLR3 agonist) and also downregulates TNF-α in human peripheral blood mononuclear cells. Mechanistically, SMU-14a reduces the phosphorylation of p65, ERK, and TBK1 through the NF-κB, MAPK, and IRF3 signaling pathways, thereby inhibiting the production of inflammatory cytokines. In vivo, SMU-14a was found to effectively decrease the release of the inflammatory factor IL-6 and reduce serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), demonstrating a potent anti-inflammatory effect and protecting the liver from internal damage. In summary, we have developed a potent Ellipticine derivative, SMU-14a, which demonstrates significant anti-inflammatory effects by blocking the NF-κB, MAPK, and IRF3 signaling pathways, thereby providing substantial hepatoprotective effects against acute hepatitis.