Cheong Dorothy Hui Juan, Yogarajah Thinesshwary, Wong Yi Hao, Arbrandt Gustav, Westman Jacob, Chu Justin Jang Hann
Infectious Disease Translational Research Programme and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Biosafety Level 3 Core Facility, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Antiviral Res. 2023 Oct;218:105713. doi: 10.1016/j.antiviral.2023.105713. Epub 2023 Aug 31.
Over the years, the hand, foot and mouth disease (HFMD) has sparked epidemics across many countries which mainly affected young children. While symptoms are usually mild, severe complications may arise, and some even lead to death. Such concerns, coupled with the lack of approved vaccines and antivirals to date, create an urgency in the identification of safe therapeutics against HFMD. The disease is mainly transmitted by enteroviruses like enterovirus A71 (EV-A71). Essential for enterovirus replication is the host protein, PI4KB. In this study, we investigate the antiviral efficacy of a novel PI4KB inhibitor, CUR-N399. We found that CUR-N399 displayed broad-spectrum antiviral activity against picornaviruses in cell culture models. Using a suckling mouse model of lethal EV-A71 infection, CUR-N399 was found to be well-tolerated, promote survival and reduce viral titre in mice organs. Together, these support the discovery of CUR-N399 as an antiviral against EV-A71 and potentially other closely related viruses.
多年来，手足口病（HFMD）在许多国家引发了疫情，主要影响幼儿。虽然症状通常较轻，但可能会出现严重并发症，有些甚至会导致死亡。这些担忧，加上迄今为止缺乏获批的疫苗和抗病毒药物，使得识别针对手足口病的安全治疗方法变得紧迫。该疾病主要由肠道病毒如肠道病毒A71（EV - A71）传播。宿主蛋白PI4KB对肠道病毒复制至关重要。在本研究中，我们研究了一种新型PI4KB抑制剂CUR - N399的抗病毒效果。我们发现CUR - N399在细胞培养模型中对微小核糖核酸病毒显示出广谱抗病毒活性。使用致死性EV - A71感染的乳鼠模型，发现CUR - N399耐受性良好，可提高小鼠存活率并降低小鼠器官中的病毒滴度。综上所述，这些结果支持了CUR - N399作为一种针对EV - A71以及可能其他密切相关病毒的抗病毒药物的发现。
