Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949

• Despite the steadily increased numbers of formyl peptide receptor (FPR) ligands identified over the years, few have been characterized in studies using animal disease models and even less have entered clinical trials in human subjects. A small-molecule compound, Act-389949, was however recently tested in a phase I clinical trial and found to be safe and well tolerated in healthy human subjects. The desired anti-inflammatory property of Act-389949 was proposed to be mediated through FPR2, one of the FPRs expressed in neutrophils, but no basic characterization was included in the study. To gain more insights into FPR2 recognition of this first-in-class compound for future utility of the agonist, we have in this study determined the receptor preference and downstream signaling characteristics induced by Act-389949 in human blood neutrophils isolated from healthy donors. Our data demonstrate that Act-389949 is an agonist for FPR2 that triggers functional/signaling repertoires comparable to what has been earlier described for other FPR2 agonists, including neutrophil chemotaxis, granule mobilization and activation of the NADPH-oxidase. In fact, Act-389949 was found to be as potent as the prototype FPR2 peptide agonist WKYMVM and had the advantage of being resistant to oxidation by MPO-H2O2 halide derived oxidants, as compared to the sensitive WKYMVM. The down-stream signals generated by Act-389949 include an FPR2-dependent and Gaq-independent transient rise in intracellular Ca2+ and recruitment of beta-arrestin. In summary, our data show that Act-389949 serves as an excellent tool-compound for further dissection of FPR2-regulated activities in vitro and in vivo. Potent and stable FPR ligands such as Act-389949 may therefore be used to develop the next generation of FPR signaling regulating anti-inflammatory therapeutics.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

Nyckelord

Neutrophils

Formyl peptide receptors

Receptor agonists

NADPH-oxidase

beta-Arrestin

Balanced agonism

chronic granulomatous-disease

formyl peptide receptors

reduced

oxidative burst

met-leu-phe

nadph-oxidase

inflammatory responses

respiratory burst

cyclosporine-h

activation

arthritis

Pharmacology & Pharmacy

Neutrophils

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)