Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
Department of Pharmaceutical and Administrative Sciences, Saint Louis College of Pharmacy, University of Health Sciences and Pharmacy, St. Louis, MO 63010, USA.
Int J Mol Sci. 2022 May 27;23(11):6044. doi: 10.3390/ijms23116044.
Hepatitis A virus (HAV) infection is a major cause of acute hepatitis worldwide and occasionally causes acute liver failure and can lead to death in the absence of liver transplantation. Although HAV vaccination is available, the prevalence of HAV vaccination is not adequate in some countries. Additionally, the improvements in public health reduced our immunity to HAV infection. These situations motivated us to develop potentially new anti-HAV therapeutic options. We carried out the in silico screening of anti-HAV compounds targeting the 3C protease enzyme using the Schrodinger Modeling software from the antiviral library of 25,000 compounds to evaluate anti-HAV 3C protease inhibitors. Additionally, in vitro studies were introduced to examine the inhibitory effects of HAV subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in hepatoma cell lines using luciferase assays and real-time RT-PCR. In silico studies enabled us to identify five lead candidates with optimal binding interactions in the active site of the target HAV 3C protease using the Schrodinger Glide program. In vitro studies substantiated our hypothesis from in silico findings. One of our lead compounds, Z10325150, showed 47% inhibitory effects on HAV genotype IB subgenomic replicon replication and 36% inhibitory effects on HAV genotype IIIA HA11-1299 replication in human hepatoma cell lines, with no cytotoxic effects at concentrations of 100 μg/mL. The effects of the combination therapy of Z10325150 and RNA-dependent RNA polymerase inhibitor, favipiravir on HAV genotype IB HM175 subgenomic replicon replication and HAV genotype IIIA HA11-1299 replication showed 64% and 48% inhibitory effects of HAV subgenomic replicon and HAV replication, respectively. We identified the HAV 3C protease inhibitor Z10325150 through in silico screening and confirmed the HAV replication inhibitory activity in human hepatocytes. Z10325150 may offer the potential for a useful HAV inhibitor in severe hepatitis A.
甲型肝炎病毒（HAV）感染是全球急性肝炎的主要病因，偶尔会导致急性肝衰竭，如果没有肝移植，可能导致死亡。虽然有 HAV 疫苗接种，但在一些国家，HAV 疫苗接种的普及率并不高。此外，公共卫生的改善降低了我们对 HAV 感染的免疫力。这些情况促使我们开发潜在的新的抗 HAV 治疗选择。我们使用 Schrodinger 建模软件，对来自 25000 种化合物的抗病毒文库中针对 3C 蛋白酶的抗 HAV 化合物进行了计算机筛选，以评估抗 HAV 3C 蛋白酶抑制剂。此外，我们引入了体外研究，使用荧光素酶测定法和实时 RT-PCR，在肝癌细胞系中研究 HAV 亚基因组复制子复制和 HAV HA11-1299 基因型 IIIA 复制的抑制作用。计算机研究使我们能够使用 Schrodinger Glide 程序，在目标 HAV 3C 蛋白酶的活性部位识别出五个具有最佳结合相互作用的先导候选物。体外研究证实了我们从计算机研究中得出的假设。我们的一种先导化合物 Z10325150 对人肝癌细胞系中 HAV 基因型 IB 亚基因组复制子的复制显示出 47%的抑制作用，对 HAV 基因型 IIIA HA11-1299 复制显示出 36%的抑制作用，在 100μg/ml 的浓度下没有细胞毒性作用。Z10325150 和 RNA 依赖性 RNA 聚合酶抑制剂利巴韦林联合治疗对 HAV 基因型 IB HM175 亚基因组复制子和 HAV 基因型 IIIA HA11-1299 复制的影响分别显示出对 HAV 亚基因组复制子和 HAV 复制的 64%和 48%的抑制作用。我们通过计算机筛选发现了 HAV 3C 蛋白酶抑制剂 Z10325150，并在人肝细胞中证实了 HAV 复制抑制活性。Z10325150 可能为严重甲型肝炎提供一种有用的 HAV 抑制剂。
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