Research for hepatitis A virus host factors using compound and gene knockout libraries

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08852
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Suzuki Ryosuke 国立感染症研究所, ウイルス第二部, 室長 (50342902)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: A型肝炎 / A型肝炎ウイルス / 治療薬

Outline of Final Research Achievements

To identify the host factors important for hepatitis A virus (HAV) infection and proliferation, we screened a library of known pharmacologically active compounds with known target proteins. As a result, we identified loxapine, which is approved by the FDA for the treatment of schizophrenia. Loxapine is an inhibitor of the dopamine D2 receptor (DRD2), but because its expression was not observed in hepatocytes where HAV proliferates and replicates, we considered that it may act without mediated DRD2. Analysis of loxapine-resistant virus mutations suggested that it acts directly on the HAV 2C protein. Furthermore, the anti-HAV effect of loxapine was observed not only in cultured cells but also in infected mouse models.

Free Research Field

ウイルス学　肝炎ウイルス　フラビウイルス

Academic Significance and Societal Importance of the Research Achievements

A型肝炎は、高齢者では症状や肝障害が重い傾向があり、劇症化し死亡する事もある。先進国でも数百人から数万人規模のアウトブレイクが生じ、死亡例も報告されており、感染や発症を制御する必要性が高まっているが、ワクチンはあるものの、特異的治療薬がない。本研究成果は2Cタンパク質が治療薬のターゲットとなる事が明らかとなり、A型肝炎治療薬開発において有用な知見となることが期待される。