AZD-2858

HBV leads to severe liver diseases, such as cirrhosis and HCC. Identification of host factors that regulate HBV replication can provide new therapeutic targets. The discovery of sodium taurocholate cotransporting polypeptide (NTCP) as an HBV entry receptor has enabled the establishment of hepatic cell lines for analyzing HBV infection and propagation. Using this new system, studies aimed at identifying host factors that regulate HBV propagation have increased.

We established an HBV-based-reporter gene expression system that mimics HBV replication from transcription to virus egress. Using this approach, we screened 1827 Food and Drug Administration–approved compounds and identified glycogen synthase kinase 3 (GSK3)alpha/beta inhibitors, including AZD1080, CHIR-98014, CHIR-98021, BIO, and AZD2858, as anti-HBV compounds. These compounds suppressed HBeAg and HBsAg production in HBV-infected human primary hepatocytes. Proteome analysis revealed that GSK3alpha/beta phosphorylated forkhead box K1/2 (FOXK1/2)s. A double-knockout of FOXK1/2 in HBV-infected HepG2-NTCP cells reduced HBeAg and HBsAg production. The rescue of FOXK2 expression, but not FOXK1 expression, in FOXK1/2-double-knockout cells restored HBeAg and HBsAg production. Importantly, phosphorylation of FOXK2 at Ser 424 is required for GSK3alpha/beta-mediated HBeAg and HBsAg production. We observed the binding of FOXK2 to HBV DNA in HepG2-NTCP cells.

Our recombinant HBV-based screening system enables the discovery of new targets. Using our approach, we identified GSK3 inhibitors as potential anti-HBV agents.

Enhanced bone healing within 1 week after post-titanium (Ti) dental implant surgery especially contributes to the subsequent long-term osseointegration, and the commonly used drug-loaded TiO₂ nanotubes (TNTs) can promote osteogenesis yet still face the challenge of burst drug release that makes it difficult to maintain long-term effective drug concentrations and good osseointegration. Here, we prepared a double drug loading/release system of silk fibroin/mesoporous silica nanoparticles (SF/MSN) nanocomposite coating modified TNTs (TAMA) with AZD2858 (Wnt/β-catenin pathway agonist for promoting osteogenesis) as the therapeutic drug, realizing a long-term stable drug release and better osteogenesis. The increased β-sheet content of SF reduced the degradation rate of the SF/MSN coating, thus avoiding the AZD2858 burst release. The adsorption of MSN maintained the effective drug concentration more than 1 week that was especially critical for early bone healing. Under the protection of SF/MSN coating, the TAMA implant showed a well-organized spatial release of AZD2858, well enabling the osteogenic differentiation and mineralization at cellular level for up to 21 days. Animal experiments further demonstrated that the slow release of AZD2858 in the TAMA implant effectively activated the Wnt/β-catenin pathway, enabling rapid bone healing in the early stage of implantation and finally achieving the best osseointegration efficacy. Thus, this study proposed an efficient strategy for developing high-performance dental implants via the construction of a biodegradable SF/MSN coating.