Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: Increased receptor specificity and in vivo activity

Complement activation plays a key role in mediating apoptosis, inflammation, and transplant rejection. In this study, the role of the complement 5a receptor (C5aR) was examined in human renal allografts and in an allogenic mouse model of renal transplant rejection. In human kidney transplants with acute rejection, C5aR expression was increased in renal tissue and in cells infiltrating the tubulointerstitium. Similar findings were observed in mice. When recipient mice were treated once daily with a C5aR antagonist before transplantation, long-term renal allograft survival was markedly improved compared with vehicle-treatment (75 versus 0%), and apoptosis was reduced. Furthermore, treatment with a C5aR antagonist significantly attenuated monocyte/macrophage infiltration, perhaps a result of reduced levels of monocyte chemoattractant protein 1 and the intercellular adhesion molecule 1. In vitro, C5aR antagonism inhibited intercellular adhesion molecule 1 upregulation in primary mouse aortic endothelial cells and reduced adhesion of peripheral blood mononuclear cells. Furthermore, C5aR blockade markedly reduced alloreactive T cell priming. These results demonstrate that C5aR plays an important role in mediating acute kidney allograft rejection, suggesting that pharmaceutical targeting of C5aR may have potential in transplantation medicine.

show abstract

“…53 Potent inhibition of human C5aR and high activity on murine C5aR makes JPE-1375 particularly suitable for testing in murine models. 52 …”

Section: C5ar Antagonistmentioning

confidence: 99%

“…52 JPE-1375 is a hexameric linear peptidomimetic molecule (molecular weight 955) that has been used previously in an experimental model of renal fibrosis in mice. 53 Potent inhibition of human C5aR and high activity on murine C5aR makes JPE-1375 particularly suitable for testing in murine models.…”

Section: C5ar Antagonistmentioning

confidence: 99%

Complement 5a Receptor Inhibition Improves Renal Allograft Survival

Gueler¹,

Rong²,

Gwinner³

et al. 2008

Journal of the American Society of Nephrology

Self Cite

105

116

View full text Add to dashboard Cite

show abstract

“…The C5aR antagonist (C5aRA) JPE-1375 was provided by Jerini AG (Berlin, Germany) and has been characterized previously (17). In brief, JPE-1375 is a hexameric linear peptidomimetic molecule (molecular weight 955) that inhibits C5a binding to the human C5aR with an IC 50 of 111 nM (in transfected HEK-293 cells).…”

Section: C5ar Antagonistmentioning

confidence: 99%

Complement C5 Mediates Experimental Tubulointerstitial Fibrosis

Konieczny¹,

Villa²,

Schult³

et al. 2007

Journal of the American Society of Nephrology

Self Cite

105

View full text Add to dashboard Cite

“…As is shown in literatures, C5a, a 74-amino acid peptide cleaved from C5 at sites of inflammation or infection during activation of the complement system (CS) (Blagg et al, 2008a(Blagg et al, , 2008b, is a broad pro-inflammatory molecule that binds to G protein-coupled receptors CD88 (C5aR) (Schnatbaum et al, 2006;Barbay et al, 2008). It has been recognized as a very potent inflammatory mediator generated during complement activation (Wong et al, 1998) and a causative or aggravating agent in a variety of inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, immune complex disease, reperfusion injury, Alzheimer's disease, ischemic heart disease, and adult respiratory distress syndrome (ARDS) (Vlattas et al, 1994;Wong et al, 1998;Finch et al, 1999;Haas et al, 2005).…”

mentioning

confidence: 99%

“…Thus, C5a is a very intriguing therapeutic target for anti-inflammatory therapy (Haas et al, 2005), blocking the action of C5a on its binding receptors may provide an effective treatment of a variety of inflammatory diseases (Lama et al, 1992;Arumugam et al, 2004, Blagg et al, 2008a, 2008b. Considerable efforts have also been directed toward the discovery of small molecule drugs capable of blocking the complement C5aR response especially, but there have been few clinically available non-peptide C5a receptor antagonists disclosed (Astles et al, 1997;Schnatbaum et al, 2006). For these reasons, it is necessary and also urgent to further understand the C5a structural features important for receptor binding and activation (Vlattas et al, 1994;Finch et al, 1997).…”

mentioning

confidence: 99%