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

This is the authors' abstract. We don't add key points for this paper.

Nirmatrelvir, the active compound of the drug Paxlovid, inhibits the Main protease of SARS-CoV-2 (M Pro , 3CL Pro , 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 50 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. • We identified a strong antiviral synergy between Nirmatrelvir, the active compound in Paxlovid, and GRP78 inhibitors. Dual inhibition of the viral protease and the ER chaperone effectively suppresses SARS-CoV-2 replication. • While Nirmatrelvir is the leading antiviral for SARS-CoV-2, its efficacy remains suboptimal. Combining it with GRP78 inhibitors could enhance treatment outcomes and drive the clinical development of GRP78-targeting drugs. • GRP78 was previously linked to virus entry, but we show its key role in intracellular virus replication. It supports viral progression when M Pro /NSP5 activity is reduced, revealing a novel therapeutic target.