Zhang Jin-Lan, Li Yu-Huan, Wang Lu-Lu, Liu Hong-Qi, Lu Shuai-Yao, Liu Yong, Li Ke, Liu Bin, Li Su-Yun, Shao Feng-Min, Wang Kun, Sheng Ning, Li Rui, Cui Jin-Jin, Sun Pei-Chun, Ma Chun-Xia, Zhu Bo, Wang Zhe, Wan Yuan-Hao, Yu Shi-Shan, Che Yongsheng, Wang Chao-Yang, Wang Chen, Zhang Qiangqian, Zhao Li-Min, Peng Xiao-Zhong, Cheng Zhenshun, Chang Jun-Biao, Jiang Jian-Dong
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
Signal Transduct Target Ther. 2021 Dec 6;6(1):414. doi: 10.1038/s41392-021-00835-6.
Azvudine (FNC) is a nucleoside analog that inhibits HIV-1 RNA-dependent RNA polymerase (RdRp). Recently, we discovered FNC an agent against SARS-CoV-2, and have taken it into Phase III trial for COVID-19 patients. FNC monophosphate analog inhibited SARS-CoV-2 and HCoV-OC43 coronavirus with an EC between 1.2 and 4.3 μM, depending on viruses or cells, and selective index (SI) in 15-83 range. Oral administration of FNC in rats revealed a substantial thymus-homing feature, with FNC triphosphate (the active form) concentrated in the thymus and peripheral blood mononuclear cells (PBMC). Treating SARS-CoV-2 infected rhesus macaques with FNC (0.07 mg/kg, qd, orally) reduced viral load, recuperated the thymus, improved lymphocyte profiles, alleviated inflammation and organ damage, and lessened ground-glass opacities in chest X-ray. Single-cell sequencing suggested the promotion of thymus function by FNC. A randomized, single-arm clinical trial of FNC on compassionate use (n = 31) showed that oral FNC (5 mg, qd) cured all COVID-19 patients, with 100% viral ribonucleic acid negative conversion in 3.29 ± 2.22 days (range: 1-9 days) and 100% hospital discharge rate in 9.00 ± 4.93 days (range: 2-25 days). The side-effect of FNC is minor and transient dizziness and nausea in 16.12% (5/31) patients. Thus, FNC might cure COVID-19 through its anti-SARS-CoV-2 activity concentrated in the thymus, followed by promoted immunity.
阿兹夫定（FNC）是一种核苷类似物，可抑制HIV-1 RNA依赖性RNA聚合酶（RdRp）。最近，我们发现FNC是一种抗新型冠状病毒（SARS-CoV-2）的药物，并已将其用于COVID-19患者的III期试验。FNC单磷酸类似物对SARS-CoV-2和人冠状病毒OC43（HCoV-OC43）具有抑制作用，其半数有效浓度（EC）在1.2至4.3μM之间，具体取决于病毒或细胞类型，选择性指数（SI）在15至83范围内。在大鼠中口服FNC显示出显著的归巢至胸腺的特性，三磷酸FNC（活性形式）集中在胸腺和外周血单个核细胞（PBMC）中。用FNC（0.07mg/kg，每日一次，口服）治疗感染SARS-CoV-2的恒河猴可降低病毒载量，恢复胸腺功能，改善淋巴细胞谱，减轻炎症和器官损伤，并减少胸部X光片上的磨玻璃影。单细胞测序表明FNC可促进胸腺功能。一项关于FNC同情用药的随机单臂临床试验（n = 31）显示，口服FNC（5mg，每日一次）治愈了所有COVID-19患者，病毒核糖核酸100%转阴时间为3.29±2.22天（范围：1至9天），出院率100%的时间为9.00±4.93天（范围：2至25天）。FNC的副作用较小，16.12%（5/31）的患者出现短暂的头晕和恶心。因此，FNC可能通过其在胸腺中集中的抗SARS-CoV-2活性治愈COVID-19，进而促进免疫力。
