Journal Article Epublish
PubMed: 40703349 DOI: 10.3389/fphar.2025.1549296
The GPR4 antagonist NE-52-QQ57 increases survival, mitigates the hyperinflammatory response and reduces viral load in SARS-CoV-2-infected K18-hACE2 transgenic mice.
Front Pharmacol 16:1549296
Authors: Xin-Jun Wu, Karen A Oppelt, Ming Fan, Mona A Marie, Madison M Swyers, Ashley J Williams, Isabelle M Lemasson, Rachel L Roper, Paul Bolin, Li V Yang
Affiliations
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
- Department of Comparative Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, United States.
Abstract
COVID-19 (Coronavirus disease 19) is caused by infection with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the respiratory system and other organ systems. Tissue injuries resulting from viral infection and host hyperinflammatory responses may lead to moderate to severe pneumonia, systemic complications, and even death. While anti-inflammatory agents have been used to treat patients with severe COVID-19, their therapeutic effects are limited. GPR4 (G protein-coupled receptor 4) is a pro-inflammatory receptor expressed on vascular endothelial cells, regulating leukocyte infiltration and inflammatory responses. In this study, we evaluated the effects of a GPR4 antagonist, NE-52-QQ57, in the SARS-CoV-2-infected K18-hACE2 transgenic mouse model. Our results demonstrated that GPR4 antagonist treatment increased the survival rate in this severe COVID-19 mouse model. The inflammatory response, characterized by proinflammatory cytokines and chemokines, was reduced in the GPR4 antagonist group compared with the vehicle group. Additionally, both SARS-CoV-2 RNA copy numbers and infectious viral titers in the mouse lung were decreased in the GPR4 antagonist group. The percentage of SARS-CoV-2 antigen-positive mouse brains was also decreased in the GPR4 antagonist group compared to the vehicle group. Furthermore, the GPR4 antagonist inhibited SARS-CoV-2 propagation in Vero E6 and Caco-2 cells. Together, these results suggest that GPR4 antagonism may be explored as a novel approach for the treatment of COVID-19 and other similar viral diseases.
MeSH
Cells, Sars-Cov-2, Viral Load, Covid-19, Therapeutics, Severe Acute Respiratory Syndrome-Related Coronavirus, Pharmaceutical Vehicles, Antiviral Agents, Infections, Virus Diseases