Abstract
The receptor for advanced glycation endproducts (RAGE) binds diverse ligands linked to chronic inflammation and disease. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. The cytoplasmic tail (ct) of RAGE is essential for RAGE ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE signaling requires interaction of ctRAGE with the intracellular effector, mammalian diaphanous 1 or DIAPH1. We screened a library of 58,000 small molecules and identified 13 small molecule competitive inhibitors of ctRAGE interaction with DIAPH1. These compounds, which exhibit in vitro and in vivo inhibition of RAGE-dependent molecular processes, present attractive molecular scaffolds for the development of therapeutics against RAGE-mediated diseases, such as those linked to diabetic complications, Alzheimer’s disease, and chronic inflammation, and provide support for the feasibility of inhibition of protein-protein interaction (PPI).
Highlights
The Receptor for Advanced Glycation Endproducts (RAGE) is a multi-ligand receptor of the immunoglobulin superfamily of cell surface molecules[1,2,3,4]
Because of the requirement to establish the veracity of the receptor for advanced glycation endproducts (RAGE) cytoplasmic domain binding to diaphanous 1 (DIAPH1) as a key mechanism of RAGE signal transduction, taken together with the fact that extracellular domain inhibition of RAGE has not yet been shown to be fully safe and efficacious in the diverse patho-biological settings characterized by RAGE actions in human disease, we focused on targeting the ctRAGE-DIAPH1 interaction
The discovery that ctRAGE bound DIAPH1 and that DIAPH1 was required for the effects of RAGE ligand stimulation in vascular and immune cells set the stage for the discovery of an entirely novel class of RAGE pathway antagonists
Summary
The Receptor for Advanced Glycation Endproducts (RAGE) is a multi-ligand receptor of the immunoglobulin superfamily of cell surface molecules[1,2,3,4]. These data suggested that knock-down of DIAPH1 expression did not impart generalized and non-specific suppression of intracellular effector pathways Based on these data indicating that DIAPH1 was required for RAGE signal transduction, solution NMR spectroscopy was used to identify interaction surfaces between ctRAGE and DIAPH1 FH1 domain. In the case of amyloid-ß-peptide, evidence suggests that the V domain is the principal recognition site for this ligand[27,28] Taken together, these examples underscore the complexity of RAGE ligand binding to the extracellular domains of the receptor. Because of the requirement to establish the veracity of the RAGE cytoplasmic domain binding to DIAPH1 as a key mechanism of RAGE signal transduction, taken together with the fact that extracellular domain inhibition of RAGE has not yet been shown to be fully safe and efficacious in the diverse patho-biological settings characterized by RAGE actions in human disease, we focused on targeting the ctRAGE-DIAPH1 interaction
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