Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg , Gothenburg (SWE).
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg , Gothenburg (SWE).
Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177 (SWE).
Department of Rheumatology and Inflammation Research, Institute of Medicine, University of Gothenburg , Gothenburg (SWE).
Show others and affiliations
2019 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 166, p. 163-173Article in journal (Refereed) Published
Abstract [en]

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 down-stream 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 Gαq-independent transient rise in intracellular Ca2+ and recruitment of β-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.

Place, publisher, year, edition, pages
2019. Vol. 166, p. 163-173
Keywords [en]
Neutrophils, Formyl peptide receptors, Receptor agonists, NADPH-oxidas, β-Arrestin, Balanced agonism
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:hv:diva-21249DOI: 10.1016/j.bcp.2019.04.030ISI: 000474498800015PubMedID: 31085160Scopus ID: 2-s2.0-85065845963OAI: oai:DiVA.org:hv-21249DiVA, id: diva2:1837517
Funder
Swedish Research CouncilVinnova, 2016-01010Vinnova, 2018-02579
Note

Green Open Access

Available from: 2024-02-14 Created: 2024-02-14 Last updated: 2024-09-19Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMedScopus

Authority records

Olofsson-Sahl, Peter

Search in DiVA

By author/editor
Olofsson-Sahl, Peter
By organisation
Grants and Innovation Office (GIO)
In the same journal
Biochemical Pharmacology
Rheumatology and Autoimmunity

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 105 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf