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

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

doi:10.1038/s41392-021-00835-6

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 EC50 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.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)belongs to the subfamily Orthocoronavirinae in the family of Coronaviridae
FNC inhibited the replication of coronaviruses in vitro FNC compound itself is almost inactive in inhibiting viral replication in vitro; it needs to be phosphorylated three times to be transferred to FNC triphosphate (FNC-TP), the active form of drug that inhibits RNA-dependent RNA polymerase (RdRp) of viruses.[15,16,17]
Anti-SARS-CoV-2 efficacy was evaluated by measuring SARS-CoV-2 viral RNA copy numbers via quantitative real-time RT-PCR and cytopathic effect (CPE) 48 h post-infection

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)belongs to the subfamily Orthocoronavirinae in the family of Coronaviridae. SARS-CoV-2 viral load of either nasal swabs or blood samples in the untreated monkeys was significantly higher than that in the FNC-treated ones (Fig. 3a), demonstrating a significant antiviral potency of FNC in vivo.

Results

Conclusion