Development of Receptor for Advanced Glycation End Products (RAGE) ligands through target directed dynamic combinatorial chemistry: a novel class of possible antagonists

• Published in: Chemistry : a European journal Vol. 30; no. 20; pp. e202303255 - n/a
• Main Authors: Dascalu, Anca‐Elena, Furman, Christophe, Landrieu, Isabelle, Cantrelle, François‐Xavier, Mortelecque, Justine, Grolaux, Gaëlle, Gillery, Philippe, Tessier, Frédéric, Lipka, Emmanuelle, Billamboz, Muriel, Boulanger, Eric, Ghinet, Alina
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 05.04.2024; Wiley Subscription Services, Inc; Wiley-VCH Verlag
• Subjects: Advanced glycosylation end products; Antagonist; Antagonists; Cell surface receptors; Chemical Sciences; Chemistry; Chemistry, Multidisciplinary; Combinatorial analysis; Combinatorial chemistry; DCC; Development strategies; ELISA; Enzyme-linked immunosorbent assay; Glyceraldehyde; Inflammageing; Inflammation; Ligands; Physical Sciences; RAGE; Receptor for Advanced Glycation End Products - chemistry; Receptor for Advanced Glycation End Products - metabolism; Receptors; Science & Technology; Signal Transduction; Therapeutic targets; Thermophoresis; ureido-N-acylhydrazones; LIBRARIES; DESIGN; RECOGNITION; DCC; ureido-N-acylhydrazones; Inflammageing; GENERATION; RAGE; Antagonist; INHIBITORS; ENDPRODUCTS
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202303255

RAGE is a transmembrane receptor of immunoglobulin family that can bind various endogenous and exogenous ligands, initiating the inflammatory downstream signaling pathways, including inflammaging. Therefore, RAGE represents an attractive drug target for age‐related diseases. For the development of small‐molecule RAGE antagonists, we employed protein‐templated dynamic combinatorial chemistry (ptDCC) using RAGE′s VC1 domain as a template, the first application of this approach in the context of RAGE. The affinities of DCC hits were validated using microscale thermophoresis. Subsequent screening against AGE2 (glyceraldehyde‐modified AGE)‐sRAGE (solubleRAGE) (AGE2‐BSA/sRAGE) interaction using ELISA tests led to the identification of antagonists with micromolar potency. Our findings not only demonstrate the successful application of ptDCC on RAGE but also highlight its potential to address the pressing need for alternative strategies for the development of small‐molecule RAGE antagonists, an area of research that has experienced a slowdown in recent years. Tackling the Receptor for Advanced Glycation End Products (RAGE) inhibition via Dynamic Combinatorial Chemistry (DCC). Leveraging protein recognition, in the presence of a continually self‐correcting, evolving dynamic library, we were able to find novel ligands for RAGE. Our biological tests confirmed their superior affinities, as well as potential as antagonists, a fresh perspective for inhibiting this multifaceted and inflammation‐associated receptor.