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
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,...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-07-01
|
| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1549296/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849703054058717184 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Xin-Jun Wu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1f06fdec00b94f809dd07cf009796109 |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj-art-1f06fdec00b94f809dd07cf0097961092025-08-20T03:17:24ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-07-011610.3389/fphar.2025.15492961549296The GPR4 antagonist NE-52-QQ57 increases survival, mitigates the hyperinflammatory response and reduces viral load in SARS-CoV-2-infected K18-hACE2 transgenic miceXin-Jun Wu0Karen A. Oppelt1Ming Fan2Mona A. Marie3Madison M. Swyers4Ashley J. Williams5Isabelle M. Lemasson6Rachel L. Roper7Paul Bolin8Li V. Yang9Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Comparative Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesDepartment of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United StatesCOVID-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.https://www.frontiersin.org/articles/10.3389/fphar.2025.1549296/fullGPR4 antagonistSARS-CoV-2COVID-19mouse modelanti-inflammationantiviral |
| spellingShingle | 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 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 Frontiers in Pharmacology GPR4 antagonist SARS-CoV-2 COVID-19 mouse model anti-inflammation antiviral |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | gpr4 antagonist ne 52 qq57 increases survival mitigates the hyperinflammatory response and reduces viral load in sars cov 2 infected k18 hace2 transgenic mice |
| topic | GPR4 antagonist SARS-CoV-2 COVID-19 mouse model anti-inflammation antiviral |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1549296/full |
| work_keys_str_mv | AT xinjunwu thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT karenaoppelt thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT mingfan thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT monaamarie thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT madisonmswyers thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT ashleyjwilliams thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT isabellemlemasson thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT rachellroper thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT paulbolin thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT livyang thegpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT xinjunwu gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT karenaoppelt gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT mingfan gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT monaamarie gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT madisonmswyers gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT ashleyjwilliams gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT isabellemlemasson gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT rachellroper gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT paulbolin gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice AT livyang gpr4antagonistne52qq57increasessurvivalmitigatesthehyperinflammatoryresponseandreducesviralloadinsarscov2infectedk18hace2transgenicmice |