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Enhanced efficacy of endonuclease inhibitor baloxavir acid against orthobunyaviruses when used in combination with ribavirin

ter Horst, Sebastiaan, Fernandez-Garcia, Yaiza, Bassetto, Marcella, Günther, Stephan, Brancale, Andrea ORCID:, Neyts, Johan and Rocha-Pereira, Joana 2020. Enhanced efficacy of endonuclease inhibitor baloxavir acid against orthobunyaviruses when used in combination with ribavirin. Journal of Antimicrobial Chemotherapy 75 (11) , pp. 3189-3193. 10.1093/jac/dkaa337

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Objectives Baloxavir acid is an endonuclease inhibitor approved for use against influenza. We evaluated whether this compound also targets the endonuclease domain of orthobunyaviruses and therefore could potentially be used against orthobunyavirus infections. Methods We performed a thermal shift assay and a fluorescence resonance energy transfer (FRET)-based nuclease monitoring assay using the La Crosse virus (LACV) endonuclease and baloxavir acid to prove their interaction and identify an inhibitory effect. Their interaction was further studied in a docking simulation using Glide SP. We show that baloxavir acid inhibits the viral replication of Bunyamwera virus (BUNV)–mCherry in vitro using high-content imaging and virus yield assay. Lastly, we investigated the use of baloxavir acid in combination with ribavirin in vitro by implementing the Zero Interaction Potency response surface model. Results We show that baloxavir acid augments LACV enzyme’s melting temperature with ΔTm 9.5 ± 0.4°C and inhibited substrate cleavage with IC50 0.39 ± 0.03 μM. Moreover, our docking simulation suggests that baloxavir acid is able to establish an efficient binding with the LACV endonuclease. In the cell-based assay, we observed that baloxavir acid and ribavirin inhibited BUNV–mCherry with an EC50 of 0.7 ± 0.2 μM and 26.6 ± 8.9 μM, respectively. When used in combination, we found a maximum synergistic effect of 8.64. Conclusions The influenza endonuclease inhibitor baloxavir acid is able to bind to and interfere with the endonuclease domain of orthobunyaviruses and yields a more potent antiviral effect than ribavirin against BUNV–mCherry. The combination of both compounds results in a more potent antiviral effect, suggesting that these molecules could potentially be combined to treat orthobunyavirus-infected patients.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Oxford University Press
ISSN: 0305-7453
Date of First Compliant Deposit: 8 September 2020
Date of Acceptance: 30 June 2020
Last Modified: 07 Jan 2024 20:52

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