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Antiviral compounds and method for treating hepatotropic viral infection, particularly hepatitis b and hepatitis d

a technology for which is applied in the field of antiviral compounds and methods for treating hepatitis b and d, can solve the problems of increasing the likelihood of liver failure, the inability of patients with hbv infection to use the currently approved anti-hbv drugs, and the inability to cure hepatitis b or d. to achieve the effect of controlling cytokines within homeostasis and inhibiting viral replication

Pending Publication Date: 2021-10-07
SENHWA BIOSCIENCES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods and compounds for treating hepatotropic viral infections. The compounds are CK2 inhibitors that can inhibit viral replication and control cytokines within homeostasis simultaneously. The compounds have the ability to inhibit the replication of hepatitis B virus (HBV) and hepatitis C virus (HCV) in humans and animals. The methods and compounds can be used to treat hepatotropic viral infections in humans and animals.

Problems solved by technology

For those chronic viral hepatitis, only hepatitis C can be cured by presently available treatments, and no currently available treatment can be applied to cure hepatitis B or hepatitis D.
An increasing number of patients with HBV infection cannot use the currently approved anti-HBV drugs, including interferon alpha or nucleos(t)ide analogues that inhibit the viral reverse transcriptase, due to the adverse effects and the emergence of drug resistance.
These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections.
Although some treatments are available for hepatitis B and hepatitis D, none of the above treatments can completely clear the virus.
Furthermore, viral resistance and cross drug resistance often result in ineffectiveness of the treatments.

Method used

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  • Antiviral compounds and method for treating hepatotropic viral infection, particularly hepatitis b and hepatitis d
  • Antiviral compounds and method for treating hepatotropic viral infection, particularly hepatitis b and hepatitis d
  • Antiviral compounds and method for treating hepatotropic viral infection, particularly hepatitis b and hepatitis d

Examples

Experimental program
Comparison scheme
Effect test

experiment 1

ty Test with the Compounds

[0196]The compounds used were SH-001, SH-002, and SH-003. Before testing their potential antiviral effect on HBV and HDV infection, we first examined their toxicity on VeroE6 cells, HepG2.2.15 cells and HuS-E / 2 immortalized human primary hepatocytes cells at concentration from 0 to 320 μM as indicated. Our results showed the CC50>204.7 μM for SH-001, CC50>61.3 μM for SH-002, and CC50>204.7 μM for SH-003 in VeroE6 cells (FIG. 1). In HepG2.2.15 cells, the CC50>194.9 μM for SH-001 and the CC50>164.1 μM for SH-002 (FIG. 2). In HuS-E / 2 cells, The CC50>194.9 μM for SH-001 and the CC50>164.1 μM for SH-002 (FIG. 3).

experiment 2

ry Effect of SH-001 and SH-002 on HBV Replication in HepG2.2.15 Cells

[0197]To test the effect of the compounds on HBV replication, SH-001 and SH-002 were added to the cell culture medium at indicated concentrations and cultured for 48 h, and then the viruses are collected from supernatant. Q-PCR was performed to detect HBV DNA as an efficiency index of HBV replication. Moreover, the HBV HBsAg and HBeAg were examined by ELISA assay. The results from ELISA assays showed that levels of HBsAg (FIGS. 4A and 5A) and HBeAg (FIGS. 4B and 5B) in the culture supernatant, which reflects the quantity of secreted HBV particles, was significantly decreased in the presence of SH-001 and SH-002. In addition, as shown in FIGS. 4C and 5C, HBV DNA was also repressed in the treatment of SH-001 and SH-002 in a dose-dependent manner. Taken together, the results showed that both SH-001 and SH-002 suppress HBV replication in HepG2.2.15 cells.

[0198]After treated HepG2.2.15 cells with 10 μM SH-001 and 10 μM ...

experiment 3

ry Effect of SH-001 and SH-002 on HDV Replication in HuS-E / 2 Cells

[0199]To investigate the effect of the compounds on HDV infection, SH-001 and SH-002 were added to the medium at indicated concentrations during HDV infection in HuS-E / 2 cells for 18 h, respectively. The infected cells were then washed and incubated in medium containing the tested compounds for further 48 h, and real-time PCR was used to detect HDV mRNA as an efficiency index of HDV infection. The results showed that SH-001 and SH-002 significantly inhibited HDV replication in HuS-E / 2 human hepatocytes.

[0200]Using 2.5 and 5 μM SH-001, HDV RNA levels were reduced to 28.8±22.8% and 8.7±1.3%, respectively, compared to in its absence (FIG. 6A) and the half-maximal inhibitory concentration (IC50) was estimated to be approximately 0.1457 μM. Using 0.1 and 0.2 μM SH-002, HDV RNA levels were reduced to 53.1±16.8% and 40.8±18.6%, respectively, compared to in its absence, and the IC50 was estimated to be approximately 0.069 μM,...

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Abstract

The present invention provides a compound or a method for treating a hepatotropic viral infection in a human, particularly hepatitis B and hepatitis D, wherein the compound is a certain tricyclic compound.

Description

CROSS REFERENCE[0001]This application claims the priority on U.S. Patent Provisional Application No. 63 / 001,723 filed on Mar. 30, 2020, and U.S. Patent Provisional Application No. 63 / 053,908 filed on Jul. 20, 2020, the entire contents of which are hereby incorporated by reference.FIELD OF THE INVENTION[0002]The present invention pertains to antiviral compounds, which is capable of treating hepatotropic viral infection, particularly caused by hepatitis virus B and D (HBV and HDV).BACKGROUND OF THE INVENTION[0003]Viral hepatitis is liver inflammation due to a viral infection. The most common causes of viral hepatitis are the infections by five hepatotropic viruses, hepatitis virus A, B, C, D, and E (HAV, HBV, HCV, HDV and HEV). Among those five hepatotropic viruses, HAV and HEV predominantly cause acute infection and will be completely cleared by the immune system, whereas the infections by HBV, HCV and HDV often become chronic. For those chronic viral hepatitis, only hepatitis C can ...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61K31/4375A61P31/14
CPCA61K31/519A61P31/14A61K31/4375Y02A50/30A61K31/4745A61K31/437A61P31/20
Inventor SOONG, TAI-SEN
Owner SENHWA BIOSCIENCES INC
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