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Methods for treating hepatitis b virus (HBV) infection

A technology for hepatitis B virus and chronic infection, which can be applied in antiviral agents, pharmaceutical formulas, medical preparations containing active ingredients, etc., and can solve problems such as unclear cell nucleus functions

Pending Publication Date: 2021-02-12
INSERM法国国家健康医学研究院 +5
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Therefore, the nuclear function of HBc remains unclear (Seeger et al., 2015)

Method used

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  • Methods for treating hepatitis b virus (HBV) infection
  • Methods for treating hepatitis b virus (HBV) infection
  • Methods for treating hepatitis b virus (HBV) infection

Examples

Experimental program
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Embodiment Construction

[0014] In this study, the inventors demonstrated that SRSF10 is a major factor present in the HBc nuclear complex and can function in the HBV life cycle. Since 1C8 has been shown to regulate the phosphorylation status of SRSF10, the inventors directly investigated whether this molecule, which has been shown to regulate HIV replication, could also inhibit HBV replication. They found that the 1C8 compound was indeed able to inhibit the replication of HBV (genotypes D and C) in persistently infected hepatocytes, strongly reducing intracellular HBV RNAs by 60-70% (see Figure 5A ), and the secretion of viral antigens (HBs and HBeAg) and HBV virions in the cell culture supernatant was reduced by 60-70% (see Figure 5B ). The IC8 compound was also able to inhibit HBV cccDNA establishment in the setting of a nascent infection: addition of this molecule in hepatocytes before and during HBV inoculation (genotypes C and D) strongly reduced cccDNA establishment (70% reduction, respective...

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Abstract

In the present invention, the proteomic identification of HBc interacting factors in the nucleus of human hepatocytes revealed a majority of RNA-binding proteins (RBPs) intervening in mRNA metabolismand especially, the serine / arginine-rich splicing factor (10) (SRSF1O) which was found enriched nearly (3000) times in HBc complexes. Inventors demonstrated that the inhibition of SRSF1O phosphorylation with the small molecule 1C8 (4- pyridinonebenzisothiazole carboxamide) induces a strong inhibition of HBV replication (genotypes C and D) in persistently-infected hepatocytes, as well as to a strong inhibition of the establishment of HBV cccDNA in de novo infection settings. Accordingly the present invention relates to an inhibitor of SRSF1O activity for use in the treatment of Hepatitis B virus (HBV) infection said inhibitor maintain SRSF1O in a dephosphorylated state and prevents or reduces the splicing activity of SRSF1O.

Description

[0001] field of invention [0002] The present invention relates to methods and pharmaceutical compositions for the treatment of hepatitis B virus infection using biologically active inhibitors of SRSF10 (serine / arginine-rich splicing factor 10), in particular said inhibitors maintain SRSF10 in a dephosphorylated state , and prevent or reduce the splicing activity of SRSF10. [0003] Background of the invention [0004] Despite the existence of preventive vaccines, chronic hepatitis B virus (HBV) infections remain a major health problem worldwide as they affect 250 million people and represent the leading cause of primary liver cancer (hepatocellular carcinoma, HCC) (Petruzziello, 2018). The current clinically recognized antiviral therapy for HBV chronic infection includes directly targeting pegylated interferon-α (IFN-α) that is transcribed from viral DNA and indirectly enhancing the host immune response and / or specifically inhibiting HBV reverse transcription. Nucleoside an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4439A61P31/20
CPCA61K31/4439A61P31/20
Inventor A·萨尔维蒂D·杜兰特H·夏布勒T·拉尔利D·格里森B·查博特
Owner INSERM法国国家健康医学研究院
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