作为口服有效的B型肝炎片组装调节器,形状受限的异诺
Eugen F Mesaros1, Andrew G Cole1, Steven G Kultgen1
1Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States.
ACS medicinal chemistry letters
|September 18, 2024
概括
新的异类化合物通过向HBV囊组合,有效抑制乙型肝炎病毒 (HBV) 复制. 优化的候选药物表现出强大的抗病毒活性和有利的药理动力学,在临床前模型中显示出显著的口服疗效.
科学领域:
- 药用化学 医学化学
- 病毒学 病毒学
- 药物发现 药物发现 药物发现
背景情况:
- 慢性乙型肝炎 (CHB) 仍然是一个重大的全球健康问题.
- 目前用于CHB的治疗方法存在局限性,需要新的治疗策略.
- 乙肝病毒囊组装调节器通过抑制病毒复制提供了一个有前途的治疗方法.
研究的目的:
- 开发和优化基于异诺林的新型HBV囊组装调节器.
- 为了研究这些化合物的结构-活性关系 (SAR).
- 评估候选药物的抗病毒疗效和药理动力学特性.
主要方法:
- 蛋白X射线晶体学被用来分析调节器对HBV核心蛋白质的结合模式.
- 基于结构的药物设计被用来引入限制,以优化结合形状.
- 细胞测试 (HepDE19) 用于确定EC50值与HBVDNA对比.
- 在体外和体内进行了ADME和药理动力学研究.
- 一个体内水力动力注射小鼠模型被用于评估口服疗效.
主要成果:
- 优化的异诺林类似物在减少HBVDNA方面实现了单位的纳米分子EC50值.
- 化合物12e在小鼠模型中以1mg/kg/天的剂量显示血清HBV DNA的3log10下降.
- 化合物表现出有利的ADME和药理动力学特征,支持口服.
- 对临床相关的HBV核心蛋白变体 (T33N,I105T) 的活性保持不变.
结论:
- 基于异诺林的HBV囊组装调节器代表了一种有前途的新型抗病毒药物.
- 基于结构的优化导致了强效和口服生物可利用的候选药物.
- 这些化合物显示出治疗慢性乙型肝炎感染的巨大潜力,包括具有耐药变异的病例.
更多相关视频
11:34A Competent Hepatocyte Model Examining Hepatitis B Virus Entry through Sodium Taurocholate Cotransporting Polypeptide as a Therapeutic Target
Published on: May 10, 2022
2.2K
05:55Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
Published on: December 21, 2019
6.7K
相关概念视频
01:29Viruses with RNA Genomes
333
RNA viruses are categorized into positive-strand, negative-strand, or double-stranded groups based on their genomic structure and replication mechanisms. This classification dictates how they exploit host cellular machinery for protein synthesis and replication. Some RNA viruses also utilize reverse transcription as part of their life cycle, further diversifying their replication strategies.Positive-Strand RNA VirusesPositive-strand RNA viruses have genomes that function directly as messenger...
333
01:52Eukaryotic Transcription Inhibitors
10.3K
Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
10.3K