Hepatitis C virus (HCV) has plus single-stranded RNA genome. The gigantic precursor protein of about 3,000 amino acids translated from the HCV RNA is cut into a virus particle-forming core protein and envelope protein, and other non-structural proteins by host cell-and virus-derived protein degrading enzymes.
The core protein is known to travel into the host cell nucleus, in addition to forming the virus particle. Recently, a strong involvement of the core protein in the onset of liver cancer in which the core protein modulates host cell functions in a variety of ways has been reported. Non-Patent Literature 1 describes, for example, HCV core protein-expressing transgenic mice developing liver cancer via fatty liver with high probability. In an effort to elucidate the molecular mechanism underlying the onset of liver cancer caused by the core protein, it has been common to identify host proteins that interact with the core protein, and analyze the functions of such proteins.
Many host proteins that interact with the core protein have been reported, including p53 (Non-Patent Literature 2), RNA helicase (Non-Patent Literature 3), STAT3 (Non-Patent Literature 4), and PA28γ (Non-Patent Literature 5).
Non-Patent Literature 5 reports that the core protein interacts with PA28γ, and localizes in the nucleus. Of note, PA28γ is known as a proteasome regulatory protein localized within the cell nucleus that interacts with 20S proteasome and improves the peptidase activity thereof. This literature also reports that the 44 to 71 amino acid region of the core protein is involved in both PA28γ binding and localization in the nucleus, and that the core protein is subject to PA28γ-dependent degradation. However, the specific mechanism underlying the involvement of the core protein in the onset of liver cancer is not fully elucidated in any of the foregoing literatures.
Patent Literature 1 discloses a screening method of a drug useful for the prevention and/or treatment of hepatitis C virus-associated disease, the method including the step of evaluating the inhibitory activity on the protein interaction between the hepatitis C virus core protein and PA28γ, and a preventive and/or therapeutic drug for hepatitis C virus-associated disease obtained by the method. However, this literature is concerned with suppressing the PA28γ-induced onset of a disease arising from the hepatitis C virus-derived core protein, specifically suppressing the progression of hepatitis conditions to fatty liver, cirrhosis, and liver cancer, and does not clarify functions that prevent hepatitis C virus infection, or suppress HCV growth. Thus, unlike antiviral drugs, the hepatitis C virus-associated disease preventive and/or therapeutic drug of this literature is not intended to suppress or reduce virus amounts, and only alleviates symptoms. Therefore, continuous administration is used, and clinical development is expected to take a long time because the persistent infection takes 10 to 15 years before developing into hepatitis C virus-associated diseases such as cirrhosis and liver cancer.
It would, however, be possible to cure HCV infections if the HCV could be cleared with the use of antiviral drugs.
Considering that the current mainstream antiviral drugs target virus replication, it is considered possible to further improve anti-viral effects with an antiviral drug that uses a new mechanism to prevent viral infection or suppress virus growth.