PDF(Pubmed)
Abstract：
Although smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.
摘要：
虽然天花已经被根除,其他正痘病毒仍然是一个公共卫生问题，例如正在进行的Mpox（以前的猴痘）全球爆发。虽然先前由美国食品和药物管理局批准的用于治疗天花的医疗对策（MCM）已被用于治疗天花，先前描述的漏洞,再加上在2022年水痘爆发期间至少一种治疗方法的令人怀疑的益处,强化了识别和开发针对正痘病毒的其他MCM的必要性.这里,我们筛选了一组Merck专有小分子,并鉴定出一种新型核苷抑制剂,该抑制剂对多种正痘病毒具有有效的广谱抗病毒活性.在严重正痘病毒感染的鼠模型中口服核苷的7天给药方案的功效测试产生了存活率的剂量依赖性增加。处理过的动物在肺和鼻腔的病变大大减少，特别是在10µg/mL给药组中。在UMM-766处理的动物中,病毒水平也显著较低。这项工作表明，这种核苷类似物具有抗正痘病毒的功效，并且可以在鼠类正痘病毒模型中预防严重的疾病。重要信息最近的猴痘病毒大流行表明正痘病毒的成员，其中还包括天花病毒，导致天花，仍然是一个公共卫生问题。虽然目前存在FDA批准的治疗方案，正痘病毒耐药株可能出现的风险非常令人担忧。因此，继续探索抗痘病毒治疗是必要的.这里,我们为鉴定抗痘病毒小分子药物的高通量筛选试验开发了模板.通过筛选可用的药物库，我们在细胞培养物中发现了一种抑制正痘病毒复制的化合物.然后我们证明了这种药物可以保护动物免受严重疾病的侵害。我们在这里的发现支持使用现有的药物库识别正痘病毒靶向药物，这些药物可以作为人类安全的产品来阻止未来的疫情爆发。
