The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. ABSTRACT The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC 90 ) was 0.47 μM, very similar to its EC 90 against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 μM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 μM AT-511 (698 ± 15 and 236 ± 14 μM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC 90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.
【저자키워드】 COVID-19, SARS-CoV-2, AT-527, AT-511, AT-9010, triphosphate, lung, 【초록키워드】 Treatment, Coronaviruses, coronavirus, Antiviral, SARS-CoV, SARS-COV-2 infection, HCoV-OC43, Remdesivir, cytotoxicity, FDA, cells, human lung, hepatitis C virus, distribution, predict, SARS-CoV-2 replication, metabolite, Coronavirus-2, pharmacokinetic, nucleotide, in vitro activity, Concentration, dose, acute respiratory syndrome, tissue, subject, treat, Huh-7 cells, pharmacokinetic data, Administered, replication of SARS-CoV-2, effective, Result, shown, inhibit, required, approved, subjects, human airway epithelial, incubated, nasal epithelial cell, 【제목키워드】 oral, potent, prodrug, Guanosine,