Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function

Biochemical Pharmacology
Xaria X LiTrent M Woodruff

Abstract

The complement fragment C5a is a core effector of complement activation. C5a, acting through its major receptor C5aR1, exerts powerful pro-inflammatory and immunomodulatory functions. Dysregulation of the C5a-C5aR1 axis has been implicated in numerous immune disorders, and the therapeutic inhibition of this axis is therefore imperative for the treatment of these diseases. A myriad of small-molecule C5aR1 inhibitors have been developed and independently characterised over the past two decades, however the pharmacological properties of these compounds has been difficult to directly compare due to the wide discrepancies in the model, read-out, ligand dose and instrumentation implemented across individual studies. Here, we performed a systematic characterisation of the most commonly reported and clinically advanced small-molecule C5aR1 inhibitors (peptidic: PMX53, PMX205 and JPE1375; non-peptide: W545011, NDT9513727, DF2593A and CCX168). Through signalling assays measuring C5aR1-mediated cAMP and ERK1/2 signalling, and β-arrestin 2 recruitment, this study highlighted the signalling-pathway dependence of the rank order of potencies of the C5aR1 inhibitors. Functional experiments performed in primary human macrophages demonstrated th...Continue Reading

Citations

Nov 27, 2020·Journal of Neuroinflammation·Nicole D Schartz, Andrea J Tenner
Jan 13, 2021·Antibodies·Fazrena Nadia Md AkhirBarbara E Rolfe
Feb 9, 2021·Frontiers in Pharmacology·Xaria X LiTrent M Woodruff
Mar 11, 2021·Pharmacological Reviews·Peter GarredTom E Mollnes
Aug 29, 2021·International Immunopharmacology·Xaria X LiTrent M Woodruff
Nov 12, 2021·Journal of Medicinal Chemistry·Declan M GormanRichard J Clark

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