Oral prodrug of remdesivir parent GS-441524 is efficacious against SARS-CoV-2 in ferrets

• Published in: Nature communications Vol. 12; no. 1; p. 6415
• Main Authors: Cox, Robert M., Wolf, Josef D., Lieber, Carolin M., Sourimant, Julien, Lin, Michelle J., Babusis, Darius, DuPont, Venice, Chan, Julie, Barrett, Kim T., Lye, Diane, Kalla, Rao, Chun, Kwon, Mackman, Richard L., Ye, Chengjin, Cihlar, Tomas, Martinez-Sobrido, Luis, Greninger, Alexander L., Bilello, John P., Plemper, Richard K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.11.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 45/23; 45/88; 45/90; 45/91; 59; 631/326/596/1296; 631/326/596/4130; 64; 96/109; Adenosine - analogs & derivatives; Adenosine - pharmacology; Animal models; Animals; Antiviral Agents - pharmacology; Antiviral drugs; Bioavailability; Cell culture; Cell Line; Chlorocebus aethiops; Coronaviruses; COVID-19; COVID-19 - drug therapy; COVID-19 - metabolism; COVID-19 - virology; Cricetinae; Disease Models, Animal; Disease transmission; Epithelium; Female; Ferrets; Humanities and Social Sciences; Humans; Intravenous administration; Life Sciences; Metabolites; multidisciplinary; Mustela; Nucleosides; Oral administration; Organoids; Prodrugs; Prodrugs - pharmacology; SARS-CoV-2 - drug effects; SARS-CoV-2 - isolation & purification; Science; Science (multidisciplinary); Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Viral diseases; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26760-4

Remdesivir is an antiviral approved for COVID-19 treatment, but its wider use is limited by intravenous delivery. An orally bioavailable remdesivir analog may boost therapeutic benefit by facilitating early administration to non-hospitalized patients. This study characterizes the anti-SARS-CoV-2 efficacy of GS-621763, an oral prodrug of remdesivir parent nucleoside GS-441524. Both GS-621763 and GS-441524 inhibit SARS-CoV-2, including variants of concern (VOC) in cell culture and human airway epithelium organoids. Oral GS-621763 is efficiently converted to plasma metabolite GS-441524, and in lungs to the triphosphate metabolite identical to that generated by remdesivir, demonstrating a consistent mechanism of activity. Twice-daily oral administration of 10 mg/kg GS-621763 reduces SARS-CoV-2 burden to near-undetectable levels in ferrets. When dosed therapeutically against VOC P.1 gamma γ, oral GS-621763 blocks virus replication and prevents transmission to untreated contact animals. These results demonstrate therapeutic efficacy of a much-needed orally bioavailable analog of remdesivir in a relevant animal model of SARS-CoV-2 infection. Remdesivir is an approved antiviral treatment for COVID-19, but it needs to be administered intravenously. Here, Cox et al . show that GS-621763, a prodrug of remdesivir parent nucleoside GS-441524 has good oral bioavailability and inhibits SARS-CoV-2 and variants of concerns in ferrets.