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AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19.
Antimicrob Agents Chemother. 2021 Mar 18; 65(4)AA

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% (EC90) was 0.47 μM, very similar to its EC90 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 EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.

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Authors+Show Affiliations

Good SS
Atea Pharmaceuticals, Inc., Boston, Massachusetts, USA good.steven@ateapharma.com.
Westover J
Department of Animal, Dairy & Veterinary Sciences, Utah State University, Logan, Utah, USA.
Jung KH
Department of Animal, Dairy & Veterinary Sciences, Utah State University, Logan, Utah, USA.
Zhou XJ
Atea Pharmaceuticals, Inc., Boston, Massachusetts, USA.
Moussa A
Atea Pharmaceuticals, Inc., Boston, Massachusetts, USA.
La Colla P
Università degli Studi di Cagliari, Monserrato, Italy.
Collu G
Università degli Studi di Cagliari, Monserrato, Italy.
Canard B
Architecture et Fonction des Macromolécules Biologiques, Marseille, France.
Sommadossi JP
Atea Pharmaceuticals, Inc., Boston, Massachusetts, USA.

MeSH

Administration, OralAnimalsAntiviral AgentsCOVID-19Cell LineCell Line, TumorChlorocebus aethiopsCoronavirus 229E, HumanCoronavirus OC43, HumanCricetinaeEpithelial CellsGuanosineGuanosine MonophosphateHumansLungPhosphoramidesProdrugsSARS-CoV-2Vero CellsVirus ReplicationCOVID-19 Drug Treatment

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33558299

Citation

Good, Steven S., et al. "AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 in Vitro and a Promising Oral Antiviral for Treatment of COVID-19." Antimicrobial Agents and Chemotherapy, vol. 65, no. 4, 2021.
Good SS, Westover J, Jung KH, et al. AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19. Antimicrob Agents Chemother. 2021;65(4).
Good, S. S., Westover, J., Jung, K. H., Zhou, X. J., Moussa, A., La Colla, P., Collu, G., Canard, B., & Sommadossi, J. P. (2021). AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19. Antimicrobial Agents and Chemotherapy, 65(4). https://doi.org/10.1128/AAC.02479-20
Good SS, et al. AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 in Vitro and a Promising Oral Antiviral for Treatment of COVID-19. Antimicrob Agents Chemother. 2021 Mar 18;65(4) PubMed PMID: 33558299.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AT-527, a Double Prodrug of a Guanosine Nucleotide Analog, Is a Potent Inhibitor of SARS-CoV-2 In Vitro and a Promising Oral Antiviral for Treatment of COVID-19. AU - Good,Steven S, AU - Westover,Jonna, AU - Jung,Kie Hoon, AU - Zhou,Xiao-Jian, AU - Moussa,Adel, AU - La Colla,Paolo, AU - Collu,Gabriella, AU - Canard,Bruno, AU - Sommadossi,Jean-Pierre, Y1 - 2021/03/18/ PY - 2020/11/25/received PY - 2021/2/3/accepted PY - 2021/2/10/pubmed PY - 2021/4/2/medline PY - 2021/2/9/entrez KW - AT-511 KW - AT-527 KW - AT-9010 KW - COVID-19 KW - SARS-CoV-2 KW - lung KW - triphosphate JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 65 IS - 4 N2 - 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% (EC90) was 0.47 μM, very similar to its EC90 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 EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/33558299/AT_527_a_Double_Prodrug_of_a_Guanosine_Nucleotide_Analog_Is_a_Potent_Inhibitor_of_SARS_CoV_2_In_Vitro_and_a_Promising_Oral_Antiviral_for_Treatment_of_COVID_19_ DB - PRIME DP - Unbound Medicine ER -