Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Antimicrob Agents Chemother. 2018 Jul 27;62(8). doi: 10.1128/AAC.00766-18. Print 2018 Aug.
Morbidity and mortality resulting from influenza-like disease are a threat, especially for older adults. To improve case management, next-generation broad-spectrum antiviral therapeutics that are efficacious against major drivers of influenza-like disease, including influenza viruses and respiratory syncytial virus (RSV), are urgently needed. Using a dual-pathogen high-throughput screening protocol for influenza A virus (IAV) and RSV inhibitors, we have identified -hydroxycytidine (NHC) as a potent inhibitor of RSV, influenza B viruses, and IAVs of human, avian, and swine origins. Biochemical polymerase assays and viral RNA sequencing revealed that the ribonucleotide analog is incorporated into nascent viral RNAs in place of cytidine, increasing the frequency of viral mutagenesis. Viral passaging in cell culture in the presence of an inhibitor did not induce robust resistance. Pharmacokinetic profiling demonstrated dose-dependent oral bioavailability of 36 to 56%, sustained levels of the active 5'-triphosphate anabolite in primary human airway cells and mouse lung tissue, and good tolerability after extended dosing at 800 mg/kg of body weight/day. The compound was orally efficacious against RSV and both seasonal and highly pathogenic avian IAVs in mouse models, reducing lung virus loads and alleviating disease biomarkers. Oral dosing reduced IAV burdens in a guinea pig transmission model and suppressed virus spread to uninfected contact animals through direct transmission. Based on its broad-spectrum efficacy and pharmacokinetic properties, NHC is a promising candidate for future clinical development as a treatment option for influenza-like diseases.
流感样疾病导致的发病率和死亡率是一个威胁，尤其是对老年人而言。为了改善病例管理，急需开发针对流感样疾病主要驱动因素（包括流感病毒和呼吸道合胞病毒[RSV]）的、具有广谱抗病毒疗效的下一代药物。我们使用针对流感 A 病毒（IAV）和 RSV 抑制剂的双病原体高通量筛选方案，鉴定出β-羟基胞苷（NHC）是 RSV、乙型流感病毒以及源自人类、禽类和猪源的 IAV 的有效抑制剂。生化聚合酶分析和病毒 RNA 测序表明，该核苷酸类似物可替代胞嘧啶掺入新生病毒 RNA 中，从而增加病毒突变频率。在存在抑制剂的情况下，病毒在细胞培养中传代不会诱导出强大的耐药性。药代动力学分析表明，该化合物具有剂量依赖性的口服生物利用度（36%至 56%），在原代人呼吸道细胞和小鼠肺组织中可维持 5'-三磷酸活性代谢物的水平，每日以 800mg/kg 体重的剂量延长给药后具有良好的耐受性。该化合物在 RSV 以及季节性和高致病性禽流感 IAV 的小鼠模型中具有口服疗效，可降低肺部病毒载量并减轻疾病生物标志物。口服给药可降低豚鼠传播模型中的 IAV 负担，并通过直接传播抑制病毒传播至未感染的接触动物。基于其广谱疗效和药代动力学特性，NHC 有望成为未来流感样疾病治疗选择的临床开发候选药物。
