Laura Bautista, Cody Sirimanotham, Jason Espinoza, Dillon Cheng, Savaş Tay, Nir Drayman
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引用次数: 0
Abstract
Herpes simplex virus type 1 (HSV-1) is a highly prevalent human pathogen that causes a range of clinical manifestations, including oral and genital herpes, keratitis, encephalitis, and disseminated neonatal disease. Despite its significant health and economic burden, there is currently only a handful of approved antiviral drugs to treat HSV-1 infection. Acyclovir and its analogs are the first-line treatment, but resistance often arises during prolonged treatment periods, such as in immunocompromised patients. Therefore, there is a critical need to identify novel antiviral agents against HSV-1. Here, we performed a drug repurposing screen, testing the ability of 1,900 safe-in-human drugs to inhibit HSV-1 infection in vitro. The screen identified decitabine, a cytidine analog that is used to treat myelodysplastic syndromes and acute myeloid leukemia, as a potent anti-HSV-1 agent. We show that decitabine is effective in inhibiting HSV-1 infection in multiple cell types, including human keratinocytes, that it synergizes with acyclovir, and acyclovir-resistant HSV-1 is still sensitive to decitabine. We further show that decitabine causes G > C and C > G transversions across the viral genome, suggesting it exerts its antiviral activity by lethal mutagenesis, although a role for decitabine's known targets, DNA methyl-transferases, has not been ruled out.
Importance: Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen with a limited arsenal of antiviral agents, resistance to which can often develop during prolonged treatment, such as in the case of immunocompromised individuals. Development of novel antiviral agents is a costly and prolonged process, making new antivirals few and far between. Here, we employed an approach called drug repurposing to investigate the potential anti-HSV-1 activity of drugs that are known to be safe in humans, shortening the process of drug development considerably. We identified a nucleoside analog named decitabine as a potent anti-HSV-1 agent in cell culture and investigated its mechanism of action. Decitabine synergizes with the current anti herpetic acyclovir and increases the rate of mutations in the viral genome. Thus, decitabine is an attractive candidate for future studies in animal models to inform its possible application as a novel HSV-1 therapy.
单纯疱疹病毒 1 型(HSV-1)是一种高度流行的人类病原体,可引起一系列临床表现,包括口腔和生殖器疱疹、角膜炎、脑炎和新生儿播散性疾病。尽管HSV-1对健康和经济造成了巨大负担,但目前只有少数几种抗病毒药物获准用于治疗HSV-1感染。阿昔洛韦及其类似物是一线治疗药物,但在长期治疗过程中,如免疫力低下的患者,往往会产生耐药性。因此,亟需找到新型抗 HSV-1 病毒药物。在这里,我们进行了一次药物再利用筛选,测试了1900种安全人用药物在体外抑制HSV-1感染的能力。筛选发现,用于治疗骨髓增生异常综合征和急性髓性白血病的胞苷类似物地西他滨是一种有效的抗 HSV-1 药物。我们的研究表明,地西他滨能有效抑制多种细胞类型(包括人类角朊细胞)中的 HSV-1 感染,它能与阿昔洛韦协同作用,而且耐阿昔洛韦的 HSV-1 对地西他滨仍然敏感。我们进一步发现,地西他滨会导致病毒基因组中 G > C 和 C > G 的逆转,这表明它是通过致命诱变来发挥其抗病毒活性的,尽管地西他滨的已知靶标 DNA 甲基转移酶的作用尚未被排除:1 型单纯疱疹病毒(HSV-1)是一种流行的人类病原体,其抗病毒药物种类有限,在长期治疗过程中,如免疫力低下的患者,往往会产生抗药性。新型抗病毒药物的开发成本高昂且耗时漫长,因此新的抗病毒药物少之又少。在这里,我们采用了一种称为药物再利用的方法,研究已知对人体安全的药物的潜在抗HSV-1活性,从而大大缩短了药物开发的过程。我们在细胞培养中发现了一种名为地西他滨的核苷类似物,它是一种有效的抗HSV-1药物,并研究了它的作用机制。地西他滨能与目前的抗疱疹病毒药物阿昔洛韦协同作用,并能提高病毒基因组的突变率。因此,地西他滨是未来在动物模型中进行研究的一个有吸引力的候选药物,可为其作为 HSV-1 新型疗法的应用提供依据。
期刊介绍:
Microbiology Spectrum publishes commissioned review articles on topics in microbiology representing ten content areas: Archaea; Food Microbiology; Bacterial Genetics, Cell Biology, and Physiology; Clinical Microbiology; Environmental Microbiology and Ecology; Eukaryotic Microbes; Genomics, Computational, and Synthetic Microbiology; Immunology; Pathogenesis; and Virology. Reviews are interrelated, with each review linking to other related content. A large board of Microbiology Spectrum editors aids in the development of topics for potential reviews and in the identification of an editor, or editors, who shepherd each collection.