Division of Gastroenterology and Hepatology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Sci Transl Med. 2010 Jan 20;2(15):15ra6. doi: 10.1126/scitranslmed.3000331.
New classes of drugs are needed to combat hepatitis C virus (HCV), an important worldwide cause of liver disease. We describe an activity of a key domain, an amphipathic helix we termed 4BAH2, within a specific HCV nonstructural protein, NS4B. In addition to its proposed role in viral replication, we validate 4BAH2 as essential for HCV genome replication and identify first-generation small-molecule inhibitors of 4BAH2 that specifically prevent HCV replication within cells. Mechanistic studies reveal that the inhibitors target 4BAH2 function by preventing either 4BAH2 oligomerization or 4BAH2 membrane association. 4BAH2 inhibitors represent an additional class of compounds with potential to effectively treat HCV.
需要新的药物类别来对抗丙型肝炎病毒(HCV),这是全球范围内导致肝脏疾病的重要原因。我们描述了一种关键结构域的活性,即我们称之为 4BAH2 的两亲性螺旋,它位于特定的丙型肝炎病毒非结构蛋白 NS4B 内。除了其在病毒复制中的预期作用外,我们还验证了 4BAH2 对 HCV 基因组复制至关重要,并确定了第一代针对 4BAH2 的小分子抑制剂,这些抑制剂可特异性地阻止细胞内的 HCV 复制。机制研究表明,抑制剂通过防止 4BAH2 寡聚化或 4BAH2 膜结合来靶向 4BAH2 功能。4BAH2 抑制剂代表了一类具有有效治疗 HCV 潜力的化合物。