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

Author information

Affiliations

  • 1. Junia, Health and Environment, Laboratory of Sustainable Chemistry and Health, F-59000, Lille, France.
      Authors
    • Dascalu AE 1, 2
    • Billamboz M 1, 2
    • Ghinet A 1, 2
    (3 authors)
  • 2. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, UMR 1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000, Lille, France.
      Authors
    • Dascalu AE 1, 2
    • Furman C 2
    • Landrieu I 2
    • Cantrelle FX 2
    • Mortelecque J 2
    • Grolaux G 2
    • Tessier F 2
    • Lipka E 2
    • Billamboz M 1, 2
    • Boulanger E 2
    • Ghinet A 1, 2
    (11 authors)
  • 3. Univ. Reims Champagne-Ardenne, Laboratory of Biochemistry and Molecular Biology CNRS/URCA UMR 7369 MEDyC, Faculty of Medicine, F-51095, Reims, France.
      Authors
    • Gillery P 3
    (1 author)

ORCIDs linked to this article

Chemistry (Weinheim an der Bergstrasse, Germany), 20 Feb 2024, 30(20):e202303255
https://doi.org/10.1002/chem.202303255 PMID: 38317623 

Abstract 

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.

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Read article at publisher's site: https://doi.org/10.1002/chem.202303255

Read article for free, from open access legal sources, via Unpaywall: https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/chem.202303255Unpaywall

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Funding 

Funders who supported this work.

Agence Nationale de la Recherche (1)