Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster Model
ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since December 2019, causing coronavirus disease 2019 (COVID-19). Although vaccines for this virus have been developed rapidly, repurposing drugs approved to treat other diseases remains an invaluable treatmen...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-02-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03044-21 |
| _version_ | 1819279478577168384 |
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| author | Shiho Chiba Maki Kiso Noriko Nakajima Shun Iida Tadashi Maemura Makoto Kuroda Yuko Sato Mutsumi Ito Moe Okuda Shinya Yamada Kiyoko Iwatsuki-Horimoto Tokiko Watanabe Masaki Imai Tammy Armbrust Ralph S. Baric Peter J. Halfmann Tadaki Suzuki Yoshihiro Kawaoka |
| author_facet | Shiho Chiba Maki Kiso Noriko Nakajima Shun Iida Tadashi Maemura Makoto Kuroda Yuko Sato Mutsumi Ito Moe Okuda Shinya Yamada Kiyoko Iwatsuki-Horimoto Tokiko Watanabe Masaki Imai Tammy Armbrust Ralph S. Baric Peter J. Halfmann Tadaki Suzuki Yoshihiro Kawaoka |
| author_sort | Shiho Chiba |
| collection | DOAJ |
| description | ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since December 2019, causing coronavirus disease 2019 (COVID-19). Although vaccines for this virus have been developed rapidly, repurposing drugs approved to treat other diseases remains an invaluable treatment strategy. Here, we evaluated the inhibitory effects of drugs on SARS-CoV-2 replication in a hamster infection model and in in vitro assays. Favipiravir significantly suppressed virus replication in hamster lungs. Remdesivir inhibited virus replication in vitro, but was not effective in the hamster model. However, GS-441524, a metabolite of remdesivir, effectively suppressed virus replication in hamsters. Co-administration of favipiravir and GS-441524 more efficiently reduced virus load in hamster lungs than did single administration of either drug for both the prophylactic and therapeutic regimens; prophylactic co-administration also efficiently inhibited lung inflammation in the infected animals. Furthermore, pretreatment of hamsters with favipiravir and GS-441524 effectively protected them from virus transmission via respiratory droplets upon exposure to infected hamsters. Repurposing and co-administration of antiviral drugs may help combat COVID-19. IMPORTANCE During a pandemic, repurposing drugs that are approved for other diseases is a quick and realistic treatment option. In this study, we found that co-administration of favipiravir and the remdesivir metabolite GS-441524 more effectively blocked SARS-CoV-2 replication in the lungs of Syrian hamsters than either favipiravir or GS-441524 alone as part of a prophylactic or therapeutic regimen. Prophylactic co-administration also reduced the severity of lung inflammation. Moreover, co-administration of these drugs to naive hamsters efficiently protected them from airborne transmission of the virus from infected animals. Since both drugs are nucleotide analogs that interfere with the RNA-dependent RNA polymerases of many RNA viruses, these findings may also help encourage co-administration of antivirals to combat future pandemics. |
| first_indexed | 2024-12-24T00:28:33Z |
| format | Article |
| id | doaj.art-b06f8d8ad736460ead83f0867cc3f591 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-24T00:28:33Z |
| publishDate | 2022-02-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-b06f8d8ad736460ead83f0867cc3f5912022-12-21T17:24:21ZengAmerican Society for MicrobiologymBio2150-75112022-02-0113110.1128/mbio.03044-21Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster ModelShiho Chiba0Maki Kiso1Noriko Nakajima2Shun Iida3Tadashi Maemura4Makoto Kuroda5Yuko Sato6Mutsumi Ito7Moe Okuda8Shinya Yamada9Kiyoko Iwatsuki-Horimoto10Tokiko Watanabe11Masaki Imai12Tammy Armbrust13Ralph S. Baric14Peter J. Halfmann15Tadaki Suzuki16Yoshihiro Kawaoka17Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USADivision of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, JapanDepartment of Pathology, National Institute of Infectious Diseases, Tokyo, JapanDepartment of Pathology, National Institute of Infectious Diseases, Tokyo, JapanDivision of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, JapanInfluenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USADepartment of Pathology, National Institute of Infectious Diseases, Tokyo, JapanDivision of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, JapanDivision of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, JapanDivision of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, JapanDivision of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, JapanDepartment of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, JapanDivision of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, JapanInfluenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USADepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAInfluenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USADepartment of Pathology, National Institute of Infectious Diseases, Tokyo, JapanInfluenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USAABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide since December 2019, causing coronavirus disease 2019 (COVID-19). Although vaccines for this virus have been developed rapidly, repurposing drugs approved to treat other diseases remains an invaluable treatment strategy. Here, we evaluated the inhibitory effects of drugs on SARS-CoV-2 replication in a hamster infection model and in in vitro assays. Favipiravir significantly suppressed virus replication in hamster lungs. Remdesivir inhibited virus replication in vitro, but was not effective in the hamster model. However, GS-441524, a metabolite of remdesivir, effectively suppressed virus replication in hamsters. Co-administration of favipiravir and GS-441524 more efficiently reduced virus load in hamster lungs than did single administration of either drug for both the prophylactic and therapeutic regimens; prophylactic co-administration also efficiently inhibited lung inflammation in the infected animals. Furthermore, pretreatment of hamsters with favipiravir and GS-441524 effectively protected them from virus transmission via respiratory droplets upon exposure to infected hamsters. Repurposing and co-administration of antiviral drugs may help combat COVID-19. IMPORTANCE During a pandemic, repurposing drugs that are approved for other diseases is a quick and realistic treatment option. In this study, we found that co-administration of favipiravir and the remdesivir metabolite GS-441524 more effectively blocked SARS-CoV-2 replication in the lungs of Syrian hamsters than either favipiravir or GS-441524 alone as part of a prophylactic or therapeutic regimen. Prophylactic co-administration also reduced the severity of lung inflammation. Moreover, co-administration of these drugs to naive hamsters efficiently protected them from airborne transmission of the virus from infected animals. Since both drugs are nucleotide analogs that interfere with the RNA-dependent RNA polymerases of many RNA viruses, these findings may also help encourage co-administration of antivirals to combat future pandemics.https://journals.asm.org/doi/10.1128/mbio.03044-21SARS-CoV-2favipiravirremdesivirGS-441524Syrian hamster |
| spellingShingle | Shiho Chiba Maki Kiso Noriko Nakajima Shun Iida Tadashi Maemura Makoto Kuroda Yuko Sato Mutsumi Ito Moe Okuda Shinya Yamada Kiyoko Iwatsuki-Horimoto Tokiko Watanabe Masaki Imai Tammy Armbrust Ralph S. Baric Peter J. Halfmann Tadaki Suzuki Yoshihiro Kawaoka Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster Model mBio SARS-CoV-2 favipiravir remdesivir GS-441524 Syrian hamster |
| title | Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster Model |
| title_full | Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster Model |
| title_fullStr | Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster Model |
| title_full_unstemmed | Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster Model |
| title_short | Co-administration of Favipiravir and the Remdesivir Metabolite GS-441524 Effectively Reduces SARS-CoV-2 Replication in the Lungs of the Syrian Hamster Model |
| title_sort | co administration of favipiravir and the remdesivir metabolite gs 441524 effectively reduces sars cov 2 replication in the lungs of the syrian hamster model |
| topic | SARS-CoV-2 favipiravir remdesivir GS-441524 Syrian hamster |
| url | https://journals.asm.org/doi/10.1128/mbio.03044-21 |
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