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

• Published in: Signal transduction and targeted therapy Vol. 6; no. 1; p. 414
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.12.2021; Nature Publishing Group
• Subjects: 692/308/153; 692/699/255; Adult; Aged; Aged, 80 and over; Animals; Antiviral Agents - administration & dosage; Azides - administration & dosage; Cancer Research; Cell Biology; Coronavirus OC43, Human - metabolism; Coronaviruses; COVID-19; COVID-19 Drug Treatment; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; DNA-directed RNA polymerase; Female; HIV; Human immunodeficiency virus; Humans; Internal Medicine; Leukocytes (mononuclear); Lymphocytes; Male; Medicine; Medicine & Public Health; Middle Aged; Nausea; Nucleoside analogs; Oncology; Oral administration; Pathology; Patients; Peripheral blood mononuclear cells; Rats; RNA polymerase; RNA-directed RNA polymerase; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Thymus; Thymus gland; Thymus Gland - metabolism; Thymus Gland - virology
• ISSN: 2059-3635; 2095-9907; 2059-3635
• 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 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.