TY - JOUR
T1 - Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction
AU - Manigrasso, Michaele B.
AU - Pan, Jinhong
AU - Rai, Vivek
AU - Zhang, Jinghua
AU - Reverdatto, Sergey
AU - Quadri, Nosirudeen
AU - DeVita, Robert J.
AU - Ramasamy, Ravichandran
AU - Shekhtman, Alexander
AU - Schmidt, Ann Marie
N1 - Funding Information:
These studies were supported by grants from the United States Public Service (R24DK103032) and Juvenile Diabetes Research Foundation International (4-2011-25). The authors gratefully acknowledge the expert assistance of Ms. Latoya Woods of the Diabetes Research Program, Department of Medicine, New York University School of Medicine, in the preparation of this manuscript.
PY - 2016/3/3
Y1 - 2016/3/3
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=84960105896&partnerID=8YFLogxK
U2 - 10.1038/srep22450
DO - 10.1038/srep22450
M3 - Article
C2 - 26936329
AN - SCOPUS:84960105896
SN - 2045-2322
VL - 6
JO - Scientific Reports
JF - Scientific Reports
M1 - 22450
ER -