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Azvudine is a thymus-homing anti-SARS-CoV-2 drug effective in treating COVID-19 patients

2021; Springer Nature; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/s41392-021-00835-6

2095-9907

Jinlan Zhang, Yuhuan Li, Lulu Wang, Hongqi Liu, Shuaiyao Lu, Yong Liu, Ke Li, Bin Liu, Suyun Li, Fengmin Shao, Kun Wang, Ning Sheng, Rui Li, Jin‐Jin Cui, Peichun Sun, Chunxia Ma, Bo Zhu, Zhe Wang, Yuan-Hao Wan, Shi‐Shan Yu, Yongsheng Che, Chaoyang Wang, Chen Wang, Qiangqian Zhang, Limin Zhao, Xiaozhong Peng, Zhenshun Cheng, Junbiao Chang, Jian‐Dong Jiang,

PARP inhibition in cancer therapy

Abstract 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 50 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.