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一种新的,小型的抗HBV化合物通过破坏HBV-RNA的稳定来降低HBsAg和HBV-DNA

Takehisa Watanabe¹, Sanae Hayashi¹, Yan Zhaoyu¹

¹Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Honjo 1-1-1, Chuo, Kumamoto, 860-8556, Japan.

Journal of gastroenterology

|February 5, 2024

概括

一种新的口服药物SAG-524通过破坏HBVRNA的稳定,有效降低乙型肝炎病毒 (HBV) DNA和HBsAg水平. 这一发现为慢性乙型肝炎感染提供了功能治疗的潜力.

科学领域:

肝病学和病毒学.
药物发现和开发药物发现和开发

背景情况:

慢性乙型肝炎病毒 (HBV) 感染的标准治疗方法,如核酸类型 (NA),有效降低病毒载荷,但很少实现功能治愈.
功能治愈被定义为B型肝炎表面抗原 (HBsAg) 的持续损失.

研究的目的:

报告SAG-524的发现,一种新的小分子抑制HBV复制的抑制剂.
评估SAG-524的抗病毒特性,选择性和安全性.

主要方法:

抗病毒活性和选择性被评估在HBV感染测定和HBV感染的人性化肝脏小鼠模型 (PXB小鼠).
SAG-524单独和与恩特卡维尔联合进行了测试.
在小鼠和非人类灵长类动物中进行了毒性研究.

主要成果:

在细胞培养中,SAG-524显示出对HBV DNA (IC50 = 0.92nM) 和HBsAg (IC50 = 1.4nM) 的强烈抑制.
SAG-524通过PAPD5.5通过缩短其多A尾部来选择性地破坏HBVRNA的稳定.
在PXB小鼠中,SAG-524显著降低了血清HBsAg和HBcrAg,估计最低有效剂量为6mg/kg/天.
与恩特卡维尔的联合治疗进一步降低了肝脏中的HBsAg和共闭圆形DNA (cccDNA),耐受性良好.
在两周内服用高达1000毫克/公斤/天剂量的SAG-524治疗的子中没有观察到显著的毒性.

结论:

SAG-524是一种新型,口服生物可用的小分子,作为HBVRNA破坏稳定剂.
SAG-524有效地降低了HBV DNA和HBsAg水平.
作为一种潜在的治疗剂,SAG-524有望在慢性乙型肝炎中实现功能治疗.

关键词:

4-皮里的化合物是4-皮里.HBV-RNA 破坏稳定的过程减少HBsAg的减少在PAPD5中使用.在SAG-52424中使用.

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