Katharina Wolf1, Helen Kühn2, Felicitas Boehm2, Lisa Gebhardt2, Markus Glaudo2, Konstantin Agelopoulos3, Sonja Ständer3, Philipp Ectors4, Dirk Zahn4, Yvonne K Riedel5, Dominik Thimm5, Christa E Müller5, Sascha Kretschmann6, Anita N Kremer6, Daphne Chien7, Nathachit Limjunyawong7, Qi Peng7, Xinzhong Dong7, Pavel Kolkhir8, Jörg Scheffel9, Mia Lykke Søgaard2, Benno Weigmann2, Markus F Neurath10, Tomasz Hawro9, Martin Metz9, Michael J M Fischer11, Andreas E Kremer12. 1. Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Nuremberg, Germany. Electronic address: katharina.b.wolf@fau.de. 2. Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Nuremberg, Germany. 3. Center for Chronic Pruritus, Department of Dermatology, University of Münster, Munich, Germany. 4. Computer Chemistry Center, Friedrich-Alexander-University Erlangen-Nürnberg, Nuremberg, Germany. 5. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, Bonn, Germany. 6. Department of Medicine 5, Friedrich-Alexander-University Erlangen-Nürnberg, Nuremberg, Germany. 7. Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Md. 8. I.M. Sechenov First Moscow State Medical University (Sechenov University), Division of Immune-Mediated Skin Diseases, Moscow, Russia; Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. 9. Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. 10. Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Nuremberg, Germany; German Center for Immunotherapy-Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany. 11. Center for Physiology and Pharmacology, University of Vienna, Vienna, Austria. 12. Department of Medicine 1, University Hospital Erlangen and Friedrich-Alexander-University Erlangen-Nürnberg, Nuremberg, Germany. Electronic address: andreas.kremer@uk-erlangen.de.
Abstract
BACKGROUND: Mas gene-related G protein-coupled receptors (MRGPRs) are a G protein-coupled receptor family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate-specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells mediating IgE-independent signaling and pseudoallergic drug reactions. OBJECTIVES: Our aim was to increase knowledge about the function and regulation of MRGPRX2/MRGPRB2, which is of major importance in prevention of drug hypersensitivity reactions and drug-induced pruritus. METHODS: To identify novel MRGPR (ant)agonists, we screened a library of pharmacologically active compounds by utilizing a high-throughput calcium mobilization assay. The identified hit compounds were analyzed for their pseudoallergic and pruritogenic effects in mice and human. RESULTS: We found a class of commonly used drugs activating MRGPRX2 that, to a large extent, consists of antidepressants, antiallergic drugs, and antipsychotics. Three-dimensional pharmacophore modeling revealed structural similarities of the identified agonists, classifying them as cationic amphiphilic drugs. Mast cell activation was investigated by using the 3 representatively selected antidepressants clomipramine, paroxetine, and desipramine. Indeed, we were able to show a concentration-dependent activation and MRGPRX2-dependent degranulation of the human mast cell line LAD2 (Laboratory of Allergic Diseases-2). Furthermore, clomipramine, paroxetine, and desipramine were able to induce degranulation of human skin and murine peritoneal mast cells. These substances elicited dose-dependent scratching behavior following intradermal injection into C57BL/6 mice but less so in MRGPRB2-mutant mice, as well as wheal-and-flare reactions following intradermal injections in humans. CONCLUSION: Our results contribute to the characterization of structure-activity relationships and functionality of MRGPRX2 ligands and facilitate prediction of adverse reactions such as drug-induced pruritus to prevent severe drug hypersensitivity reactions.
BACKGROUND: Mas gene-related G protein-coupled receptors (MRGPRs) are a G protein-coupled receptor family responsive to various exogenous and endogenous agonists, playing a fundamental role in pain and itch sensation. The primate-specific family member MRGPRX2 and its murine orthologue MRGPRB2 are expressed by mast cells mediating IgE-independent signaling and pseudoallergic drug reactions. OBJECTIVES: Our aim was to increase knowledge about the function and regulation of MRGPRX2/MRGPRB2, which is of major importance in prevention of drug hypersensitivity reactions and drug-induced pruritus. METHODS: To identify novel MRGPR (ant)agonists, we screened a library of pharmacologically active compounds by utilizing a high-throughput calcium mobilization assay. The identified hit compounds were analyzed for their pseudoallergic and pruritogenic effects in mice and human. RESULTS: We found a class of commonly used drugs activating MRGPRX2 that, to a large extent, consists of antidepressants, antiallergic drugs, and antipsychotics. Three-dimensional pharmacophore modeling revealed structural similarities of the identified agonists, classifying them as cationic amphiphilic drugs. Mast cell activation was investigated by using the 3 representatively selected antidepressants clomipramine, paroxetine, and desipramine. Indeed, we were able to show a concentration-dependent activation and MRGPRX2-dependent degranulation of the human mast cell line LAD2 (Laboratory of Allergic Diseases-2). Furthermore, clomipramine, paroxetine, and desipramine were able to induce degranulation of human skin and murine peritoneal mast cells. These substances elicited dose-dependent scratching behavior following intradermal injection into C57BL/6 mice but less so in MRGPRB2-mutant mice, as well as wheal-and-flare reactions following intradermal injections in humans. CONCLUSION: Our results contribute to the characterization of structure-activity relationships and functionality of MRGPRX2 ligands and facilitate prediction of adverse reactions such as drug-induced pruritus to prevent severe drug hypersensitivity reactions.
Authors: Pavel Kolkhir; Daniel Elieh-Ali-Komi; Martin Metz; Frank Siebenhaar; Marcus Maurer Journal: Nat Rev Immunol Date: 2021-10-05 Impact factor: 53.106
Authors: Shuhui Lim; Nicolas Boyer; Nicole Boo; Chunhui Huang; Gireedhar Venkatachalam; Yu-Chi Angela Juang; Michael Garrigou; Hung Yi Kristal Kaan; Ruchia Duggal; Khong Ming Peh; Ahmad Sadruddin; Pooja Gopal; Tsz Ying Yuen; Simon Ng; Srinivasaraghavan Kannan; Christopher J Brown; Chandra S Verma; Peter Orth; Andrea Peier; Lan Ge; Xiang Yu; Bhavana Bhatt; Feifei Chen; Erjia Wang; Nianyu Jason Li; Raymond J Gonzales; Alexander Stoeck; Brian Henry; Tomi K Sawyer; David P Lane; Charles W Johannes; Kaustav Biswas; Anthony W Partridge Journal: Chem Sci Date: 2021-11-25 Impact factor: 9.825