Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green Monkeys

Mackman, R. L.; Kalla, R.; Babusis, D.; Pitts, J.; Barrett, K. T.; Chun, K.; Du Pont, V.; Rodriguez, L.; Moshiri, J.; Xu, Y.; Lee, M.; Lee, G.; Bleier, B.; Nguyen, A.-Q.; O'Keefe, B. M.; Ambrosi, A.; Cook, M.; Yu, J.; Dempah, K. E.; Bunyan, E.; Riola, N. C.; Lu, X.; Liu, R.; Davie, A.; Hsiang, T.-Y.; Gale, M.; Niedziela-Majka, A.; Feng, J. Y.; Hedskog, C.; Bilello, J. P.; Subramanian, R.; Cihlar, T.

doi:10.1101/2023.04.28.538473

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bioRxiv · 10.1101/2023.04.28.538473

Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green Monkeys

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Abstract

Remdesivir 1 is an amidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1 have prompted interest in oral approaches to generate 2-NTP. Here we describe the discovery of a 5-isobutyryl ester prodrug of 2 (GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and three to seven-fold improved oral delivery of 2 in monkeys. Prodrug 3 is cleaved pre-systemically to provide high systemic exposures of 2 that overcome its less efficient metabolism to 2-NTP leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350-400 mg twice-daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2 which supports development of 3 as a promising COVID-19 treatment.

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Mackman, R. L., Kalla, R., Babusis, D., Pitts, J., Barrett, K. T., Chun, K., Du Pont, V., Rodriguez, L., Moshiri, J., Xu, Y., Lee, M., Lee, G., Bleier, B., Nguyen, A.-Q., O'Keefe, B. M., Ambrosi, A., Cook, M., Yu, J., Dempah, K. E., Bunyan, E., Riola, N. C., Lu, X., Liu, R., Davie, A., Hsiang, T.-Y., Gale, M., Niedziela-Majka, A., Feng, J. Y., Hedskog, C., Bilello, J. P., Subramanian, R., Cihlar, T.. 2023-04-28. Discovery of GS-5245 (Obeldesivir), an Oral Prodrug of Nucleoside GS-441524 that Exhibits Antiviral Efficacy in SARS-CoV-2 Infected African Green Monkeys. https://doi.org/10.1101/2023.04.28.538473

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