Asunto(s)
COVID-19/genética , Interacciones Huésped-Patógeno/genética , Macaca mulatta/virología , Fosfoproteínas/genética , SARS-CoV-2/patogenicidad , Animales , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/inmunología , Humanos , Hígado/inmunología , Hígado/patología , Hígado/virología , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Macaca mulatta/genética , Macaca mulatta/inmunología , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/inmunología , Especificidad de Órganos , Fosfoproteínas/clasificación , Fosfoproteínas/inmunología , Proteómica/métodos , SARS-CoV-2/genética , SARS-CoV-2/crecimiento & desarrollo , SARS-CoV-2/inmunología , Transducción de Señal , Carga ViralRESUMEN
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.