Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses
Orally Efficacious Broad-Spectrum Ribonucleoside Analog Inhibitor of Influenza and Respiratory Syncytial Viruses
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DOI：
10.1128/aac.00766-18
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发表时间：
2018-08-01
影响因子：
4.9
通讯作者：
Plemper, Richard K.
中科院分区：
文献类型：
--
作者：
Yoon, Jeong-Joong;Toots, Mart;Plemper, Richard K.
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，迫切需要能够有效对抗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））的下一代广谱抗病毒疗法。使用甲型流感病毒 (IAV) 和 RSV 抑制剂的双病原体高通量筛选方案，我们已确定 N-4-羟基胞苷 (NHC) 是 RSV、乙型流感病毒以及人、禽和猪来源的 IAV 的有效抑制剂。体外生化聚合酶测定和病毒RNA测序表明，核糖核苷酸类似物代替胞苷掺入新生病毒RNA中，增加了病毒诱变的频率。在存在抑制剂的情况下，病毒在细胞培养物中的传代不会诱导强大的耐药性。药代动力学分析表明，剂量依赖性口服生物利用度为 36% 至 56%，活性 5'-三磷酸合成代谢物在原代人气道细胞和小鼠肺组织中保持水平，并且以 800 mg/kg 体重/天延长给药后具有良好的耐受性。该化合物口服对小鼠模型中的 RSV 以及季节性和高致病性禽类 IAV 有效，可减少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，并抑制病毒通过直接传播传播至未感染的接触动物。基于其广谱功效和药代动力学特性，NHC 是未来临床开发作为流感样疾病治疗选择的有希望的候选者。
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 N-4-hydroxycytidine (NHC) as a potent inhibitor of RSV, influenza B viruses, and lAVs of human, avian, and swine origins. Biochemical in vitro 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 lAVs 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.