Baloxavir-oseltamivir combination therapy inhibits the emergence of resistant substitutions in influenza A virus PA gene in a mouse model

Park, Jihyun; Kim, Beomkyu; Antigua, Khristine Joy C.; Jeong, Ju Hwan; Kim, Chang il; Choi, Won-Suk; Oh, Sol; Kim, Chan Hyung; Kim, Eung‐Gook; Choi, Young Ki; Baek, Yun Hee; Song, Min‐Suk

doi:10.1016/j.antiviral.2021.105126

Cited by 16 publications

(12 citation statements)

References 17 publications

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“…Therefore, a continuous virus monitoring and susceptibility testing of BXM is required. As previously reported, BXM/OSP combination therapy reduced the frequency of the emergence of BXM-resistant strains in H1N1pdm09 virus-infected mice compared with BXM monotherapy [69]. BXM/OSP combination therapy may also be a useful option to reduce the emergence of BXM-resistant H5N1 viruses.…”

Section: Discussionsupporting

confidence: 55%

Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against H5 Highly Pathogenic Avian Influenza Virus Infection

Taniguchi

Ando

Kobayashi

et al. 2022

Viruses

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Human infections caused by the H5 highly pathogenic avian influenza virus (HPAIV) sporadically threaten public health. The susceptibility of HPAIVs to baloxavir acid (BXA), a new class of inhibitors for the influenza virus cap-dependent endonuclease, has been confirmed in vitro, but it has not yet been fully characterized. Here, the efficacy of BXA against HPAIVs, including recent H5N8 variants, was assessed in vitro. The antiviral efficacy of baloxavir marboxil (BXM) in H5N1 virus-infected mice was also investigated. BXA exhibited similar in vitro activities against H5N1, H5N6, and H5N8 variants tested in comparison with seasonal and other zoonotic strains. Compared with oseltamivir phosphate (OSP), BXM monotherapy in mice infected with the H5N1 HPAIV clinical isolate, the A/Hong Kong/483/1997 strain, also caused a significant reduction in viral titers in the lungs, brains, and kidneys, thereby preventing acute lung inflammation and reducing mortality. Furthermore, compared with BXM or OSP monotherapy, combination treatments with BXM and OSP using a 48-h delayed treatment model showed a more potent effect on viral replication in the organs, accompanied by improved survival. In conclusion, BXM has a potent antiviral efficacy against H5 HPAIV infections.

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Section: Discussionsupporting

confidence: 55%

Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against H5 Highly Pathogenic Avian Influenza Virus Infection

Taniguchi

Ando

Kobayashi

et al. 2022

Viruses

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“…However, if a substitution such as PA/E23K is present in the initial infection, no antiviral treatment is likely to provide a virological benefit. A serial passaging study in mice has also shown that baloxavir-oseltamivir can reduce the de novo emergence of variants with reduced susceptibility to either drug ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

Effect of Baloxavir and Oseltamivir in Combination on Infection with Influenza Viruses with PA/I38T or PA/E23K Substitutions in the Ferret Model

Koszalka

George

Vijaykrishna

et al. 2022

mBio

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“…The background resistance to treatment by currently approved NAIs is growing [ 9 ], and this indicates a need for more research on other possible drug targets of influenza virus, and a need to develop additional inhibitory drugs to current targets like NA [ 2 , 9 ]. Interestingly, combination therapy with oseltamivir and the recently approved PA endonuclease inhibitor baloxavir [ 83 ] has been shown to reduce the emergence of resistant influenza viruses in a mouse model [ 84 ].…”

Section: Discussionmentioning

confidence: 99%

Optimisation of Neuraminidase Expression for Use in Drug Discovery by Using HEK293-6E Cells

Campbell

Tanner

Krause

2021

Viruses

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Influenza virus is a highly contagious virus that causes significant human mortality and morbidity annually. The most effective drugs for treating influenza are the neuraminidase inhibitors, but resistance to these inhibitors has emerged, and additional drug discovery research on neuraminidase and other targets is needed. Traditional methods of neuraminidase production from embryonated eggs are cumbersome, while insect cell derived protein is less reflective of neuraminidase produced during human infection. Herein we describe a method for producing neuraminidase from a human cell line, HEK293-6E, and demonstrate the method by producing the neuraminidase from the 1918 H1N1 pandemic influenza strain. This method produced high levels of soluble neuraminidase expression (>3000 EU/mL), was enhanced by including a secretion signal from a viral chemokine binding protein, and does not require co-expression of additional proteins. The neuraminidase produced was of sufficient quantity and purity to support high resolution crystal structure determination. The structure solved using this protein conformed to the previously reported structure. Notably the glycosylation at three asparagine residues was superior in quality to that from insect cell derived neuraminidase. This method of production of neuraminidase should prove useful in further studies, such as the characterisation of inhibitor binding.

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Baloxavir-oseltamivir combination therapy inhibits the emergence of resistant substitutions in influenza A virus PA gene in a mouse model

Cited by 16 publications

References 17 publications

Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against H5 Highly Pathogenic Avian Influenza Virus Infection

Characterization of the In Vitro and In Vivo Efficacy of Baloxavir Marboxil against H5 Highly Pathogenic Avian Influenza Virus Infection

Effect of Baloxavir and Oseltamivir in Combination on Infection with Influenza Viruses with PA/I38T or PA/E23K Substitutions in the Ferret Model

Optimisation of Neuraminidase Expression for Use in Drug Discovery by Using HEK293-6E Cells

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