Development of a long-acting halogenated HBV capsid inhibitor that is potent against drug-resistant HBV mutants

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K21609
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Mitsuya Hiroaki 国立研究開発法人国立国際医療研究センター, その他部局等, 研究所長 (20136724)
• Project Period (FY): 2020-07-30 – 2022-03-31
• Keywords: HBV / 慢性B型肝炎 / 薬剤耐性HBV変異株 / HBVキャプシド阻害剤 / 新規抗HBV剤の開発

Outline of Final Research Achievements

We designed, synthesized, and identified novel HBV capsid composition-inhibiting compounds, and determined 50% inhibitory concentration (IC50) values and 50% cytotoxicity concentration (CC50) values. A compound GRL-07-19 (CC50 = 27 μM, IC50 = 0.007 μM), which has a selectivity index comparable to a previously reported compound/GLS4 (IC50 = 0.015 μM; CC50 = 55 μM), and GRL-12-19 (CC50> 100 μM, IC50 = 0.004 μM) were identified.

Free Research Field

感染症内科学、血液内科学

Academic Significance and Societal Importance of the Research Achievements

ハロゲン化HBVキャプシド阻害剤候補化合物のデザイン・合成・活性評価で既報化合物GLS4(CC50 =55μM, IC50 =0.015μM),に近い良好な活性を発揮する新規化合物GRL-12-19 (CC50 >100μM, IC50 =0.004μM)を見出した。本化合物は有望なリード化合物になる可能性があり、更なる薬剤開発に重要な情報を提供する点で学術的および社会的意義が高いと考える。