Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

Hongbo Guo; Dan Liu; Kuan Liu; Yao Hou; Chunyang Li; Qiudi Li; Xiaohui Ding; Monique M. A. Verstegen; Jikai Zhang; Lingli Wang; Yibo Ding; Renxian Tang; Xiucheng Pan; Kuiyang Zheng; Luc J. W. van der Laan; Qiuwei Pan; Wenshi Wang

doi:10.1016/j.virs.2023.11.006

February 2024

. doi: 10.1016/j.virs.2023.11.006

Citation: Hongbo Guo, Dan Liu, Kuan Liu, Yao Hou, Chunyang Li, Qiudi Li, Xiaohui Ding, Monique M. A. Verstegen, Jikai Zhang, Lingli Wang, Yibo Ding, Renxian Tang, Xiucheng Pan, Kuiyang Zheng, Luc J. W. van der Laan, Qiuwei Pan, Wenshi Wang. Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions .VIROLOGICA SINICA, 2024, 39(1) : 123-133. http://dx.doi.org/10.1016/j.virs.2023.11.006

药物筛选发现维多氟拉迪莫和吡唑霉素是治疗戊型肝炎的新型候选药物

郭虹波 ^a,, ,
刘丹 ^a ,
刘宽 ^b,c ,
侯瑶 ^a ,
李春阳 ^a ,
李球棣 ^a ,
丁晓慧 ^a ,
Monique M A Verstegen ^c ,
张继凯 ^a ,
王灵丽 ^a ,
丁奕博 ^a ,
汤仁仙 ^a ,
潘修成 ^d ,
郑葵阳 ^a ,
Luc J W van der Laan ^c ,
潘秋卫 ^b,, ,
王文世 ^a,,

a. 徐州医科大学基础医学院;
b. 荷兰伊拉斯姆斯大学胃肠病和肝病系;
c. 荷兰伊拉斯姆斯大学外科系;
d. 徐州医科大学附属医院感染科

通讯作者： 郭虹波, hongbo.guo@xzhmu.edu.cn; 潘秋卫, q.pan@erasmusmc.nl; 王文世, wenshi.wang@xzhmu.edu.cn
收稿日期： 2023-08-05
录用日期： 2023-11-16

摘要

戊型肝炎病毒（hepatitis E virus,HEV）感染可引起严重的并发症和高死亡率，尤其是在孕妇、器官移植受者、或肝病患者和免疫抑制患者中。然而，目前仍缺乏治疗慢性戊型肝炎病毒感染的特定疗法。本研究通过筛选262种药物/化合库鉴定发现vidofludimus calcium和pyrazofurin为新型抗HEV小分子药物。Vidofludimus calcium是新一代二氢乳清酸脱氢酶（DHODH）抑制剂，用于治疗自身免疫性疾病或SARS-CoV-2感染（临床二期、三期）。Pyrazofurin选择性靶向尿苷单磷酸合成酶（UMPS）。在一系列细胞培养模型和不同个体人原代肝脏类器官模型中vidofludimus calcium和pyrazofurin都具有显著的抗HEV作用。并且两种药物均能高效抑制野生型HEV菌株和利巴韦林治疗失败相关的HEV毒株（Y1320H，G1634R）。令人鼓舞的是，针对HEV这两种药物都表现出相当大的的治疗窗口。例如，vidofludimus calcium的抑制HEV复制的IC50值比目前临床应用给患者的治疗剂量低4.6--7.6倍。两种药物的抗HEV作用机制是通过阻断宿主细胞嘧啶的从头合成通路。此外，vidofludimus calcium和pyrazofurin与IFN-α联合用药可产生协同抗病毒功效。总之，本研究确定vidofludimus calcium和pyrazofurin是治疗HEV感染的有效候选药物。基于其抗病毒效力，以及临床研究中确定的良好安全性，本研究结果支持启动临床研究，将这些药物用于治疗慢性戊型肝炎。
- 戊型肝炎病毒（HEV）
- , 药物再利用
- , vidofludimus calcium
- , pyrazofurin
- , 嘧啶合成

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

a. Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Immunity and Metabolism, Jiangsu International Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, 221004, China;
b. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, NL-3015 CN, the Netherlands;
c. Department of Surgery, Erasmus MC Transplant Institute, University Medical Center, Rotterdam, 3015CE, NL-3015 CN, the Netherlands;
d. Department of Infectious Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

Corresponding author: Hongbo Guo, hongbo.guo@xzhmu.edu.cn Qiuwei Pan, q.pan@erasmusmc.nl Wenshi Wang, wenshi.wang@xzhmu.edu.cn
Received Date: 05 August 2023
Accepted Date: 16 November 2023

Abstract

Hepatitis E virus (HEV) infection can cause severe complications and high mortality, particularly in pregnant women, organ transplant recipients, individuals with pre-existing liver disease and immunosuppressed patients. However, there are still unmet needs for treating chronic HEV infections. Herein, we screened a best-in-class drug repurposing library consisting of 262 drugs/compounds. Upon screening, we identified vidofludimus calcium and pyrazofurin as novel anti-HEV entities. Vidofludimus calcium is the next-generation dihydroorotate dehydrogenase (DHODH) inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 infection. Pyrazofurin selectively targets uridine monophosphate synthetase (UMPS). Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV strains. Encouragingly, both drugs exhibited a sizeable therapeutic window against HEV. For instance, the IC₅₀ value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in patients. Mechanistically, their anti-HEV mode of action depends on the blockage of pyrimidine synthesis. Notably, two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants (Y1320H, G1634R). Their combination with IFN-α resulted in synergistic antiviral activity. In conclusion, we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV infections. Based on their antiviral potency, and also the favorable safety profile identified in clinical studies, our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.
- Hepatitis E virus (HEV)
- , Drug repurposing
- , Vidofludimus calcium
- , Pyrazofurin
- , Pyrimidine biosynthesis

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