Inhibition of the Src kinase family pathway as a method of treating HBV infection and hepatocellular carcinoma

Abstract

The present invention relates to therapeutic protocols and pharmaceutical compositions designed to target HBx mediated activation of Src kinase, members of the Src tyrosine kinase family and components of the Src kinase family signal transduction pathways for the treatment of HBV infection and related disorders and diseases, such as HCC. The invention further relates to pharmaceutical compositions for the treatment of HBV infection targeted to HBx and its essential activities required to sustain HBV replication. The invention is based, in part, on the Applicants' discovery that activation of Src kinase signaling cascades play a fundamental role in mammalian hepadnavirus replication. Applicants have demonstrated that HBx mediates activation of the Src family of kinases and that this activation is a critical function provided by HBx for mammalian hepadnavirus replication.

Description

1. INTRODUCTION[0001] The present invention relates to therapeutic protocols and pharmaceutical compositions designed to target Src family kinases and components of the Src kinase family signal transduction pathways, including HBx activation of Src kinase family signal transduction pathways for the treatment and prevention of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). The invention also relates to screening assays to identify potential antiviral agents which target HBx-mediated activation of Src kinase signaling cascades for the treatment of HBV.2. BACKGROUND OF THE INVENTION[0002] 2.1 Hepatitis B Virus[0003] Infection with HBV is an international public health problem of wide proportions. It has been estimated that at least 10% of the population of tropical Africa and Far-East Asia are chronic carriers of the virus (Tiollais et al., 1985, Nature 317:489-495). HBV is a hepatotropic virus whose course of infection can range from inapparent to acute hepatiti...

AI Technical Summary

Benefits of technology

[0016] The Applicants have demonstrated that HBx mediated activation of Src kinase signaling cascade is an effective target for HBV anti-viral agents since activation of this pathway is essential for HBV replication. Therefore, targeting HBx for the treatment of HBV should result in a highly specific and efficacious method of blocking HBV replication. The Src family of kinases, although host cell gene products, are only activated in proliferating or differentiating cells, and in cells infected by many DNA and tumor viruses. Therefore, targeting the Src family of kinases for the treatment of HBV infection should result in a therapeutic with a high degree of efficacy and sufficient specificity with side effects no more toxic than chemotherapeutics currently used to treat cancer.

Problems solved by technology

Infection with HBV is an international public health problem of wide proportions.

Acute hepatitis following a primary infection with HBV is usually self-limited in adults and often asymptomatic.

Furthermore, chronic HBV infection frequently results in premature death from hepatic cirrhosis and liver failure (Ganem et al., 1987, Ann. Rev. Biochem. 56: 651-693).

However, no clear mechanism has been described for the association between HCC and infection with HBV.

There are currently very limited therapeutics available for the treatment of HBV infection.

However, in contrast to the other viral polypeptides, the role of HBx in the HBV life cycle is not yet understood.

However, these results remain controversial, as other groups have found no significant liver disease in HBx expressing mice (Balsano et al., 1994, J. Hepatol. 21:103-109; Dandri et al., 1996, J. Virol. 70; Lee et al., 1990, J. Virol. 64:5939-5947).

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