NH115a, anovel inhibitor of the La protein: Effect on expression of multiple RNAs in hepatitis B virus-infected hepatoma cells and embryotoxicity profile.

Abstract

The La protein binds to RNA and protects replication of the hepatitis B virus (HBV). We recently developed the compound nH115a, an inhibitor of the La protein that has high stability and anti-HBV activity. However, the mechanism, by which this compound inhibits HBV infection and its safety to embryos, remains unclear. Our goal was to examine the molecular mechanism, by which nH115a inhibits HBV infection, and to characterize its embryotoxicity. Microarray experiments using HepG2.2.15 cells (established by transfecting an HBV plasmid into HepG2 hepatoma cells) and bioinformatics analyses were used to measure the effect of nH115a on the expression of lncRNAs, mRNAs, and circRNAs. The embryonic stem cell test was used to assess the embryotoxicity of nH115a. nH115a significantly altered the expression of 2402 lncRNAs, 338 mRNAs, and 559 circRNAs. Gene Ontology (GO) analysis indicated the differentially expressed transcripts functioned in interleukin-2 production, I-SMAD binding, RNA-induced silencing complex (RISC), NLRP3 inflammasome complex assembly, cytoplasmic sequestering of nuclear factor kappa-B (NF-κB), and death receptor binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated the most enriched pathways included transforming growth factor-β (TGF-β) signaling, pathways in cancer, ubiquitin mediated proteolysis, p53 signaling, antigen processing and presentation, Fc gamma R-mediated phagocytosis, and B cell receptor signaling. The results of the embryonic stem cell test indicated that nH115a exhibited weak embryotoxicity. In conclusion, immune responses, TGF-β/SMAD signaling, and cancer-related pathways may function in the nH115a-mediated inhibition of HBV replication. Keywords: hepatitis B virus; La protein; inhibitor; nH115a.