The proteolytically-activated G protein-coupled receptor (GPCR) protease-activated receptor 2 (PAR2), is implicated in various cancers and inflammatory diseases. Synthetic ligands and in vitro imaging probes targeting this receptor have been developed with low nanomolar affinity, however, no in vivo imaging probes exist for PAR2. Here, we report the strategic design, synthesis, and biological evaluation of a series of novel 4-fluorobenzoylated PAR2-targeting peptides derived from 2f-LIGRLO-NH (2f-LI-) and Isox-Cha-Chg-Xaa-NH (Isox-) peptide families, where the 4-fluorobenzoyl moiety acts as the F-standard of an F-labeled probe for potential use in in vivo imaging. We found that several of the 4-fluorobenzoylated peptides from the 2f-LI-family exhibited PAR2 selectivity with moderate potency (EC = 151-252 nM), whereas several from the Isox-family exhibited PAR2 selectivity with high potency (EC = 13-42 nM). Our lead candidate, Isox-Cha-Chg-Ala-Arg-Dpr(4FB)-NH (EC = 13 nM), was successfully synthesized with fluorine-18 with a radiochemical yield of 37%, radiochemical purity of >98%, molar activity of 20 GBq/μmol, and an end of synthesis time of 125 min. Biodistribution studies and preliminary PET imaging of the tracer in mice showed predominantly renal clearance. This F-labeled tracer is the first reported PAR2 imaging agent with potential for use in vivo. Future work will explore the use of this tracer in cancer xenografts and inflammation models involving upregulation of PAR2 expression.
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http://dx.doi.org/10.1016/j.ejmech.2022.114989 | DOI Listing |
J Biomol Struct Dyn
January 2025
Laboratory of Biology and Health, URAC 34, Faculty of Sciences, Ben M'Sik Hassan II University of Casablanca, Casablanca, Morocco.
The recent spread of SARS-CoV-2 has led to serious concerns about newly emerging infectious coronaviruses. Drug repurposing is a practical method for rapid development of antiviral agents. The viral spike protein of SARS-CoV-2 binds to its major receptor ACE2 to promote membrane fusion.
View Article and Find Full Text PDFSemin Thromb Hemost
January 2025
Department of Neurology, Sheba Medical Center, Tel Ha'Shomer, Israel.
Coagulation factors are intrinsically expressed in various brain cells, including astrocytes and microglia. Their interaction with the inflammatory system is important for the well-being of the brain, but they are also crucial in the development of many diseases in the brain such as stroke and traumatic brain injury. The cellular effects of coagulation are mediated mainly by protease-activated receptors.
View Article and Find Full Text PDFCell Discov
January 2025
Guangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, MOE Engineering Center of South China Sea Marine Biotechnology, Southern Laboratory of Ocean Science and Engineering (Zhuhai), State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
Apoptotic protease activating factor 1 (Apaf-1) was traditionally defined as a scaffold protein in mammalian cells for assembling a caspase activation platform known as the 'apoptosome' after its binding to cytochrome c. Although Apaf-1 structurally resembles animal NOD-like receptor (NLR) and plant resistance (R) proteins, whether it is directly involved in innate immunity is still largely unknown. Here, we found that Apaf-1-like molecules from lancelets, fruit flies, mice, and humans have conserved DNA sensing functionality.
View Article and Find Full Text PDFBMJ Open Respir Res
January 2025
Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Background: The most common cause of death in those with cystic fibrosis (CF) is respiratory failure due to bronchiectasis resulting from repeated cycles of respiratory infection and inflammation. Protease-activated receptor 1 (PAR1) is a cell surface receptor activated by serine proteases including neutrophil elastase, which is recognised as a potent modulator of inflammation. While PAR1 is known to play an important role in regulating inflammation, nothing is known about any potential role of this receptor in CF pathogenesis.
View Article and Find Full Text PDFCureus
January 2025
Obstetrics and Gynecology, Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, CHN.
Objective: The present study was designed to comprehensively analyze the expression profiles of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), estrogen-related receptor-α (ERRα), estrogen receptor-β (ERβ), interleukin-6 (IL-6), cysteinyl-aspartic acid-specific protease-3 (caspase-3), and cysteinyl-aspartic acid-specific protease-9 (caspase-9) in endometriosis tissues. It also aimed to elucidate the hitherto unclarified role of PGC-1α in the processes of proliferation, apoptosis, and gene expression regulation of human endometrial stromal cells, thereby providing novel insights and identifying potential molecular targets for advancing endometriosis treatment modalities.
Methods: A total of 49 ectopic endometrial tissue samples and 50 normal endometrial tissue samples were meticulously collected from patients who underwent gynecological surgeries in the People's Hospital Affiliated to Fujian University of Traditional Chinese Medicine in Fuzhou, China, between January 2022 and January 2023.
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