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

Ralph S. Baric¹  Tokiko Watanabe²  Yuko Sato³  Shun Iida³  Noriko Nakajima³  Tadaki Suzuki³  Tadashi Maemura⁴  Moe Okuda⁴  Shinya Yamada⁴  Masaki Imai⁴  Maki Kiso⁴  Kiyoko Iwatsuki-Horimoto⁴  Mutsumi Ito⁴  Makoto Kuroda⁵  Yoshihiro Kawaoka⁵  Shiho Chiba⁵  Peter J. Halfmann⁵  Tammy Armbrust⁵ 

[1] Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA;Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan;Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan;Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Wisconsin, USA;

关键词: SARS-CoV-2;    favipiravir;    remdesivir;    GS-441524;    Syrian hamster;   

DOI  :  10.1128/mbio.03044-21

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown