CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
J Med Chem. 2020 Jun 11;63(11):5972-5989. doi: 10.1021/acs.jmedchem.0c00232. Epub 2020 May 20.
Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, (, EC = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that is long-lasting, is orally available, and has low toxicity in vivo. These results show as a promising HCV entry inhibitor for single or combinational therapeutic potential.
虽然直接作用抗病毒药物在过去十年中彻底改变了丙型肝炎病毒 (HCV) 感染的治疗方法，但在没有疫苗的情况下，仍需要做出更多努力来消除 HCV。4-(哌嗪-1-基)-2-((-甲苯氨基)甲基)-苯甲腈 (1) 是一种适度的 HCV 抑制剂，它是从使用 HCV 感染的 Huh7.5 细胞培养物进行的内部筛选中鉴定出来的。从它出发，通过化学优化提供了一种新的 2-((4-芳基哌嗪-1-基)甲基)苯甲腈支架，对 HCV 的抗病毒活性显著提高。通过结构-活性关系研究，鉴定出一种高效的 HCV 抑制剂 (，EC = 0.022 μM，SI > 600)。该化合物的生物学研究表明，它可以通过作用于 HCV 进入阶段来阻断 HCV 复制。该化合物对临床耐药 HCV 突变体高度敏感，与临床药物具有协同作用。进一步的药物研究表明， 在体内具有长效、可口服和低毒性。这些结果表明 作为一种有前途的 HCV 进入抑制剂，具有单药或联合治疗的潜力。
