tetano
Editor, Senior Moderator
Antiviral Res
. 2025 Jul 29:106247.
doi: 10.1016/j.antiviral.2025.106247. Online ahead of print. The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication
Doha Al Krad[SUP] 1 [/SUP], Kim M Stegmann[SUP] 1 [/SUP], Antje Dickmanns[SUP] 1 [/SUP], Priya Kumar[SUP] 1 [/SUP], Claudia Blaurock[SUP] 2 [/SUP], Björn-Patrick Mohl[SUP] 2 [/SUP], Sina Jasmin Wille[SUP] 1 [/SUP], Angele Breithaupt[SUP] 2 [/SUP], Tobias Britzke[SUP] 2 [/SUP], Anne Balkema-Buschmann[SUP] 2 [/SUP], Matthias Dobbelstein[SUP] 3 [/SUP]
Affiliations
Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (M[SUP]Pro[/SUP], 3CL[SUP]Pro[/SUP], 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, TCID[SUB]50[/SUB] titers, and reduced accumulation of the non-structural proteins, 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.
Keywords: 3CL(Pro); COVID-19; Calu-3 cells; Coronavirus; ER-stress; Endoplasmic Reticulum; GRP78; Golden Syrian hamster; HA15; M(Pro); NSP5; Nirmatrelvir; Paxlovid; Protease; SARS-CoV-2; Vero E6 cells.
. 2025 Jul 29:106247.
doi: 10.1016/j.antiviral.2025.106247. Online ahead of print. The protease inhibitor Nirmatrelvir synergizes with inhibitors of GRP78 to suppress SARS-CoV-2 replication
Doha Al Krad[SUP] 1 [/SUP], Kim M Stegmann[SUP] 1 [/SUP], Antje Dickmanns[SUP] 1 [/SUP], Priya Kumar[SUP] 1 [/SUP], Claudia Blaurock[SUP] 2 [/SUP], Björn-Patrick Mohl[SUP] 2 [/SUP], Sina Jasmin Wille[SUP] 1 [/SUP], Angele Breithaupt[SUP] 2 [/SUP], Tobias Britzke[SUP] 2 [/SUP], Anne Balkema-Buschmann[SUP] 2 [/SUP], Matthias Dobbelstein[SUP] 3 [/SUP]
Affiliations
- PMID: 40744403
- DOI: 10.1016/j.antiviral.2025.106247
Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (M[SUP]Pro[/SUP], 3CL[SUP]Pro[/SUP], 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, TCID[SUB]50[/SUB] titers, and reduced accumulation of the non-structural proteins, 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.
Keywords: 3CL(Pro); COVID-19; Calu-3 cells; Coronavirus; ER-stress; Endoplasmic Reticulum; GRP78; Golden Syrian hamster; HA15; M(Pro); NSP5; Nirmatrelvir; Paxlovid; Protease; SARS-CoV-2; Vero E6 cells.