A research group led by Professor Yasuhito Tanaka, Assistant Professor Takehisa Watanabe, and Specially Appointed Assistant Professor Sanae Hayashi of the Faculty of Life Sciences at Kumamoto University has announced that they have developed "SAG-524," a new potent and orally bioavailable small-molecule compound that inhibits hepatitis B surface (HBs) antigen and HB virus (HBV) replication in the blood. By destabilizing HBV-RNA, SAG-524 can greatly reduce the amounts of viral DNA and surface antigen (HBs antigen: An antigen on the HBV surface). The results are expected to contribute to a functional cure for chronic HB. The work was published in the April issue of the Journal of Gastroenterology.
HBV is a cause of liver diseases such as chronic HB, hepatic cirrhosis, and hepatocellular carcinoma, infecting over 290 million people worldwide and killing more than 680,000 of them each year. HBV is a DNA virus that infects the liver and can cause acute and chronic hepatitis. Once infected, HBV is difficult to eliminate and is a leading cause of hepatic cirrhosis and hepatocellular carcinoma. As a result, the therapeutic goal has been the quiescence of viral replication, for which the disappearance of HBV-DNA and the viral protein HBs antigen from the blood is a clinical indicator. In particular, eliminating HBs antigen has been shown to reduce the risk of liver carcinogenesis. Meanwhile, nucleic acid analogs, used as first-line drugs, potently inhibit HBV-DNA, but have limited efficacy in lowering (eliminating) HBs antigen in the blood. Thus, novel therapeutic agents are needed.
In this study, the research group screened 30,000 different compounds to search for drug candidates that reduce the amounts of HBs antigen and HBV-DNA in the culture supernatant. For this screening, the compounds were added to a culture medium of HBV-infected human hepatocytes (PXB cells) and human hepatocytes stably producing HBV, which are models of HBV-infected cells. After further optimization of the drug candidates, "SAG-524" was developed as a low-toxicity compound capable of potently reducing HBV-DNA and HBs antigen at very low concentrations.
Analysis of its mechanism of action revealed that it exerts the anti-HBV effect by destabilizing intracellular HBV-RNA, which is the starting point for the production of both HBV-DNA and HBs antigen, making it more susceptible to degradation. Further analysis of the mechanism of HBV-RNA destabilization suggested that SAG-524 inhibits the function of PAPD5, a poly(A) polymerase that stabilizes HBV-RNA.
To investigate the anti-HBV effect of SAG-524 in vivo, a combination therapy experiment was conducted using HB mice models, which are HBV-infected chimeric mice with the humanized liver. In the experiment, SAG-524 and the nucleic acid analog entecavir (ETV) were administered orally to the HB mice models. As a result, the serum HBV-DNA reduction was greater than that in mice treated with ETV monotherapy, and HBs antigen was also reduced. A safety study, in which SAG-524 was administered orally to monkeys showed no apparent toxicity even at high doses up to 1000 mg/kg/day. Currently, the research group is preparing for clinical trials of SAG-524, a new, highly safe drug that can be administered orally.
Tanaka said, "The HB drug discovery research project was launched to meet the expectations of patient groups, and hepatitis researchers in Japan have put the best of their efforts into it. There are great expectations for developing the safe oral drug we identified in the project."
Journal Information
Publication: Journal of Gastroenterology
Title: A novel, small anti-HBV compound reduces HBsAg and HBV-DNA by destabilizing HBV-RNA
DOI: 10.1007/s00535-023-02070-y
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