Interdisciplinary Bioengineering Graduate Program, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
School of Physics, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.
ACS Infect Dis. 2024 Apr 12;10(4):1162-1173. doi: 10.1021/acsinfecdis.3c00479. Epub 2024 Apr 2.
Hepatitis B virus (HBV) is the leading cause of chronic liver pathologies worldwide. HBV nucleocapsid, a key structural component, is formed through the self-assembly of the capsid protein units. Therefore, interfering with the self-assembly process is a promising approach for the development of novel antiviral agents. Applied to HBV, this approach has led to several classes of capsid assembly modulators (CAMs). Here, we report structurally novel CAMs with moderate activity and low toxicity, discovered through a biophysics-guided approach combining docking, molecular dynamics simulations, and a series of assays with a particular emphasis on biophysical experiments. Several of the identified compounds induce the formation of aberrant capsids and inhibit HBV DNA replication in vitro, suggesting that they possess modest capsid assembly modulation effects. The synergistic computational and experimental approaches provided key insights that facilitated the identification of compounds with promising activities. The discovery of preclinical CAMs presents opportunities for subsequent optimization efforts, thereby opening new avenues for HBV inhibition.
乙型肝炎病毒 (HBV) 是全球慢性肝脏疾病的主要病因。HBV 核衣壳是关键的结构组成部分，通过衣壳蛋白单位的自组装形成。因此，干扰自组装过程是开发新型抗病毒药物的一种有前途的方法。将该方法应用于 HBV，已经产生了几类衣壳组装调节剂 (CAMs)。在这里，我们报告了通过结合对接、分子动力学模拟以及一系列特别强调生物物理实验的测定的生物物理指导的方法发现的具有中等活性和低毒性的新型结构 CAMs。鉴定出的几种化合物可诱导异常衣壳的形成并抑制 HBV 在体外的 DNA 复制，这表明它们具有适度的衣壳组装调节作用。协同的计算和实验方法提供了关键的见解，有助于鉴定具有有前途活性的化合物。临床前 CAMs 的发现为后续的优化工作提供了机会，从而为 HBV 抑制开辟了新途径。
