AT-13148

Background: Dengue virus (DENV) infection, caused by serotypes DENV 1-4, represents a significant global public health challenge, with no antiviral drugs currently available for treatment. The host Protein kinase B (AKT) signaling pathway is crucial for DENV infection, presenting a potential target for antiviral drug development. Objective: This study aimed to evaluate the antiviral activity of kinase inhibitors that target the AKT pathway, focusing on the compound AT13148. Methods: A mini-screening was conducted to identify kinase inhibitors with antiviral properties against DENV-2. The effects of AT13148 on viral RNA replication and translation were assessed in a dose- and time-dependent manner following DENV-2 entry. The mechanism of action was further investigated by evaluating the impact of AT13148 on AKT kinase activity and phosphorylation status. Results: AT13148 exhibited potent antiviral activity against DENV-2, significantly inhibiting viral RNA replication and translation post-entry. The compound was found to inhibit AKT kinase activity through hyperphosphorylation. Conclusion: The findings indicate that AT13148 effectively targets the AKT pathway, demonstrating potential as an antiviral therapeutic against DENV-2 by interfering with the virus's post-entry processes. Further in vivo studies are warranted to assess the efficacy of AT13148 in controlling DENV infection.

Zinc finger protein 471 (ZNF471) is a member of the Krüppel-related domain zinc finger protein family, and has recently attracted attention because of its anti-cancer effects. N-glycosylation regulates expression and functions of the protein. This study aimed to investigate the effects of ZNF471 N-glycosylation on the proliferation, invasion, and docetaxel sensitivity of tongue squamous cell carcinoma (TSCC). It analyzed the expression, function, and prognostic significance of ZNF471 in TSCC using bioinformatics techniques such as gene differential expression analysis, univariate Cox regression analysis, functional enrichment analysis, and gene set enrichment analysis. Using site-specific mutagenesis, this study generated three mutant sites for ZNF471 N-glycosylation to determine the effect of N-glycosylation on ZNF471 protein levels and function. Quantitative real-time PCR, Western blot analysis, and immunohistochemistry tests confirmed the down-regulation of ZNF471 expression in TSCC. Low expression of ZNF471 is associated with poor prognosis of patients with TSCC. Overexpression of ZNF471 in vitro retarded the proliferation of TSCC cells and suppressed cell invasion and migration ability. Asparagine 358 was identified as a N-glycosylation site of ZNF471. Suppressing N-glycosylation of ZNF471 enhanced the protein stability and promoted the translocation of protein to the cell nucleus. ZNF471 binding to c-Myc gene promoter suppressed oncogene c-Myc expression, thereby playing the anti-cancer effect and enhancing TSCC sensitivity to docetaxel. In all, N-glycosylation of ZNF471 affects the proliferation, invasion, and docetaxel sensitivity of TSCC via regulation of c-Myc.