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Abstract
Hepatitis B virus (HBV) is a noncytopathic human hepadnavirus that causes acute, chronic hepatitis and hepatocellular carcinoma (HCC). As the clinical utility of current therapies is limited, new anti-HBV agents and sources for such agents are still highly sought after. Here, we report that Mucroporin-M1, a scorpion venom-derived peptide, reduces the amount of extracellular HBsAg, HBeAg, and HBV DNA productions of HepG2.2.15 cells in a dose-dependent manner and inhibits HBV capsid DNA, HBV intracellular RNA replication intermediates and the HBV Core protein in the cytoplasm of HepG2.2.15 cells. Using a mouse model of HBV infection, we found that HBV replication was significantly inhibited by intravenous injection of the Mucroporin-M1 peptide. This inhibitory activity was due to a reduction in HBV promoter activity caused by a decrease in the binding of HNF4α to the precore/core promoter region. Furthermore, we confirmed that Mucroporin-M1 could selectively activate mitogen-activated protein kinases (MAPKs) and lead to the down-regulation of HNF4α expression, which explains the decreased binding of HNF4α to the HBV promoter. Moreover, when the protein phosphorylation activity of the MAPK pathway was inhibited, both HNF4α expression and HBV replication recovered. Finally, we proved that treatment with the Mucroporin-M1 peptide increased phosphorylation of the MAPK proteins in HBV-harboring mice. These results implicate Mucroporin-M1 peptide can activate the MAPK pathway and then reduce the expression of HNF4α, resulting in the inhibition of HBV replication in vitro and in vivo. Our work also opens new doors to discovering novel anti-HBV agents or sources.
Highlights
Peptides from the scorpion venom were screened for the capacity to inhibit Hepatitis B virus (HBV) replication in the HepG2.2.15 cell line
Incubation with the Mucroporin-M1 peptide resulted in an ϳ80% reduction in the amount of HBeAg and a 70% reduction in the amount of HBsAg present in the culture medium compared with cultures not exposed to the peptide, and incubation with the Ctry2801 peptide resulted in an ϳ40% reduction in the amount of HBsAg in the culture medium
When the upstream inhibitors of the mitogen-activated protein kinases (MAPKs) pathway (PD98059, SP600125, or SB203580), which inhibit extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase (JNK), and p38, respectively, were added to HepG2.2.15 cells prior to Mucroporin-M1 treatment, we found that ERK1/2 phosphorylation was mostly inhibited and that the phosphorylation of p38 and JNK was completely blocked (Fig. 5B)
Summary
Results: Mucroporin-M1 peptide activates the MAPK pathway, and reduces the expression of HNF4␣, resulting in the inhibition of HBV replication in vitro and in vivo. Using a mouse model of HBV infection, we found that HBV replication was significantly inhibited by intravenous injection of the Mucroporin-M1 peptide This inhibitory activity was due to a reduction in HBV promoter activity caused by a decrease in the binding of HNF4␣ to the precore/core promoter region. We found that the Mucroporin-M1 peptide activated MAPKs in mouse hepatocytes, similar to the results from human hepatoma cells These data suggest that a natural animal-derived peptide, Mucroporin-M1, inhibits HBV replication by activating the MAPK pathway and down-regulating HNF4␣ expression in vitro and in vivo
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