Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier

SARS-CoV-2 is the causative agent of the immune response-driven disease COVID-19 for which new antiviral and anti-inflammatory treatments are urgently needed to reduce recovery time, risk of death and long COVID development. Here, we demonstrate that the immunoregulatory kinase p38 MAPK is activated during viral entry, mediated by the viral spike protein, and drives the harmful virus-induced inflammatory responses. Using primary human lung explants and lung epithelial organoids, we demonstrate that targeting p38 signal transduction with the selective and clinically pre-evaluated inhibitors PH-797804 and VX-702 markedly reduced the expression of the pro-inflammatory cytokines IL6, CXCL8, CXCL10 and TNF-α during infection, while viral replication and the interferon-mediated antiviral response of the lung epithelial barrier were largely maintained. Furthermore, our results reveal a high level of drug synergism of both p38 inhibitors in co-treatments with the nucleoside analogs Remdesivir and Molnupiravir to suppress viral replication of the SARS-CoV-2 variants of concern, revealing an exciting and novel mode of synergistic action of p38 inhibition. These results open new avenues for the improvement of the current treatment strategies for COVID-19.

 

Comments：

The findings  suggest that targeting the p38 MAPK pathway could be a promising strategy to reduce the harmful inflammatory responses associated with SARS-CoV-2 infection.

It's also interesting to note that the p38 inhibitors PH-797804 and VX-702 were able to reduce the expression of pro-inflammatory cytokines while maintaining the antiviral response of the lung epithelial barrier. This suggests that p38 inhibition could be a selective and targeted approach to dampen inflammation without compromising the immune response against the virus.

The observed synergism of p38 inhibition with Remdesivir and Molnupiravir to suppress viral replication is also exciting and suggests that combining these treatments could potentially have a greater therapeutic effect than each treatment alone.

Overall, these findings provide important insights into the pathogenesis of COVID-19 and potential new treatment strategies. However, further studies are needed to confirm these results and assess the safety and efficacy of p38 inhibitors in COVID-19 patients.

Related Products

Cat.No.	Product Name	Information
S2726	PH-797804	PH-797804 is a novel pyridinone inhibitor of p38α with IC50 of 26 nM in a cell-free assay; 4-fold more selective versus p38β and does not inhibit JNK2. Phase 2.

Related Targets

p38 MAPK