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TitleOral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease.
Journal, issue, pagesActa Pharmacol Sin, Vol. 46, Issue 7, Page 1958-1973, Year 2025
Publish dateMar 11, 2025
AuthorsWen-Sheng Yang / Qing Liu / Yang Li / Guan-Yi Li / Shi Lin / Jie Li / Lin-Yu Li / Yuan Li / Xi-Lin Ge / Xiao-Zhen Wang / Wei Wu / Jun Yan / Guang-Fei Wang / Qing-Tong Zhou / Qiang Liu / Ming-Wei Wang / Zhi-Ping Li /
PubMed AbstractCurrent treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents ...Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents to treat IBD are not available but potential targets like formyl peptide receptor 2 (FPR2/ALX) may fill the gap. In this study we evaluated the therapeutic effects of two small molecule FPR2/ALX modulators (agonist Quin-C1 and antagonist Quin-C7) against IBD. We first analyzed the cryo-electron microscopy structure of the Quin-C1-FPR2 in complex with heterotrimeric G to reveal the structural basis for ligand recognition and FPR2 activation. We then established dextran sulfate sodium (DSS)-induced colitis model in both normal and myeloid depletion mice. We showed that oral administration of Quin-C1 for 7 days ameliorated DSS-induced colitis evidenced by alleviated disease activity indexes, reduced colonic histopathological scores, and corrected cytokine disorders. Meanwhile, we found that oral administration of FPR2/ALX antagonist Quin-C7 exerted therapeutic actions similar to those of Quin-C1. In terms of symptomatic improvements, the ED values of Quin-C1 and Quin-C7 were 1.3660 mg/kg and 2.2110 mg/kg, respectively. The underlying mechanisms involved ERK- or ERK/JNK-mediated myeloid cell regulation that limited the development of colitis and inflammation. This is the first demonstration of anti-colitis property caused by synthetic small molecule FPR2/ALX modulators, implying that FPR2/ALX modulation rather than agonism alone ameliorates IBD.
External linksActa Pharmacol Sin / PubMed:40069490 / PubMed Central
MethodsEM (single particle)
Resolution2.58 Å
Structure data

EMDB-39915, PDB-8zbw:
Cryo-EM structure of formyl peptide receptor 2/C1R receptor in complex with Gi
Method: EM (single particle) / Resolution: 2.58 Å

Chemicals

PDB-1l1d:
Crystal structure of the C-terminal methionine sulfoxide reductase domain (MsrB) of N. gonorrhoeae pilB

Source
  • Homo sapiens (Human) (human)
  • homo sapiens (human)
KeywordsSTRUCTURAL PROTEIN / Cryo-EM / formyl peptide receptor 2 / C1R

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