ArticleProceedings of the National Academy of Sciences of the United States of America2011
Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it, 117 citations in OpenAlex.
- Characterization and Functions of Protease-Activated Receptor 2 in Obesity, Diabetes, and Metabolic Syndrome: A Systematic Review.BioMed research international · 2016Pooled it
- Coagulation protease-activated receptor-2 (PAR2) promotes dyslipidemia, obesity and MASLD through repression of the hepatic pioneer factor HNF4α.JHEP reports : innovation in hepatology · 2026Article
- Protease-Activated Receptor-2 Promotes Metastasis: An Emerging Therapeutic Target.Molecular cancer research : MCR · 2026Review
- A neurotensin receptor type 1-derived pepducin acts as a biased allosteric modulator to regulate target receptor function.Acta pharmaceutica Sinica. B · 2026Article
- Exploring the Chemical Features and Biomedical Relevance of Cell-Penetrating Peptides.International journal of molecular sciences · 2024Review
- New Target(s) for RNF43 Regulation: Implications for Therapeutic Strategies.International journal of molecular sciences · 2024Review
- Genome editing ofActa pharmaceutica Sinica. B · 2024Article
- Low-Dose Trypsin Accelerates Wound HealingACS pharmacology & translational science · 2024Article
- PARting Neuroinflammation with Protease-Activated Receptor 2 Pepducins.The Journal of pharmacology and experimental therapeutics · 2024Article
- Protease-Activated Receptor 2 in inflammatory skin disease: current evidence and future perspectives.Frontiers in immunology · 2024Review
- C781, a β-Arrestin Biased Antagonist at Protease-Activated Receptor-2 (PAR2), Displays in vivo Efficacy Against Protease-Induced Pain in Mice.The journal of pain · 2023Article
- Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands.International journal of molecular sciences · 2023Review
- Protease-activated receptors in health and disease.Physiological reviews · 2023Review
- Tryptase and Exogenous Trypsin: Mechanisms and Ophthalmic Applications.Journal of inflammation research · 2023Review
- Diversification of PAR signaling through receptor crosstalk.Cellular & molecular biology letters · 2022Review
- Proteinase-activated receptor-2 antagonist C391 inhibits Alternaria-induced airway epithelial signalling and asthma indicators in acute exposure mouse models.British journal of pharmacology · 2022Article
- Lipopeptide Pepducins as Therapeutic Agents.Methods in molecular biology (Clifton, N.J.) · 2022Article
- The PAR2 inhibitor I-287 selectively targets GαCommunications biology · 2020Article
- Targeting of G-protein coupled receptors in sepsis.Pharmacology & therapeutics · 2020Review
- PAR2 controls cholesterol homeostasis and lipid metabolism in nonalcoholic fatty liver disease.Molecular metabolism · 2019Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Protease-activated receptor-2 (PAR2), a cell surface receptor for trypsin-like proteases, plays a key role in a number of acute and chronic inflammatory diseases of the joints, lungs, brain, gastrointestinal tract, and vascular systems. Despite considerable effort by the pharmaceutical industry, PAR2 has proven recalcitrant to targeting by small molecule inhibitors, which have been unable to effectively prevent the interaction of the protease-generated tethered ligand with the body of the receptor. Here, we report the development of first-in-class cell-penetrating lipopeptide "pepducin" antagonists of PAR2. The design of the third intracellular (i3) loop pepducins were based on a structural model of a PAR2 dimer and by mutating key pharmacophores in the receptor intracellular loops and analogous pepducins. Individual pharmacophores were identified, which controlled constitutive, agonist, and antagonist activities. This approach culminated in the identification of the P2pal-18S pepducin which completely suppressed trypsin and mast cell tryptase signaling through PAR2 in neutrophils and colon cancer cells. The PAR2 pepducin was highly efficacious in blocking PAR2-dependent inflammatory responses in mouse models. These effects were lost in PAR2-deficient and mast-cell-deficient mice, thereby validating the specificity of the pepducin in vivo. These data provide proof of concept that PAR2 pepducin antagonists may afford effective treatments of potentially debilitating inflammatory diseases and serve as a blueprint for developing highly potent and specific i3-loop-based pepducins for other G protein-coupled receptors (GPCRs).
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.