The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication

Al Krad, D.; Stegmann, K. M.; Dickmanns, A.; Blaurock, C.; Mohl, B.-P.; Wille, S. J.; Breithaupt, A.; Britzke, T.; Balkema-Buschmann, A.; Dobbelstein, M.

doi:10.1101/2025.03.09.642200

bioRxiv · 10.1101/2025.03.09.642200

The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication

Al Krad, D.·Stegmann, K. M.·Dickmanns, A.·Blaurock, C.·Mohl, B.-P.·Wille, S. J.·Breithaupt, A.·Britzke, T.·Balkema-Buschmann, A.·Dobbelstein, M.

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Abstract

Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (MPro, 3CLPro, NSP5). Its therapeutic application reduces but does not abolish the progression of COVID-19 in humans. Here we report a strong synergy of Nirmatrelvir with inhibitors of the ER chaperone GRP78 (HSPA5, BiP). Combining Nirmatrelvir with the GRP78-antagonizing drug candidate HA15 strongly inhibits the replication of SARS-CoV-2, to a far greater extent than either drug alone, as observed by diminished cytopathic effect, levels of detectable virus RNA, TCID50 titers, accumulation of the non-structural protein 3 (NSP3), as well as Spike and N proteins. The original SARS-CoV-2 strain as well as an Omicron variant were similarly susceptible towards the drug combination. Other GRP78 inhibitors or siRNAs targeting GRP78 also fortified the antiviral effect of Nirmatrelvir. In a hamster model of COVID-19, the combination of Nirmatrelvir with HA15 alleviated pneumonia-induced pulmonary atelectasis more effectively than the single drugs. In conclusion, inhibition of the virus Main protease and cellular GRP78 cooperatively diminishes virus replication and may improve COVID-19 therapy.

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Al Krad, D., Stegmann, K. M., Dickmanns, A., Blaurock, C., Mohl, B.-P., Wille, S. J., Breithaupt, A., Britzke, T., Balkema-Buschmann, A., Dobbelstein, M.. 2025-03-11. The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication. https://doi.org/10.1101/2025.03.09.642200

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