1. Screening a Molecular Fragment Library to Modulate the PED/PEA15-Phospholipase D1 Interaction in Cellular Lysate Environments
- Author
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Carla Isernia, Emilia Pedone, Marica Sassano, Luigi Russo, Annarita Del Gatto, Gianluca D'Abrosca, Sonia Di Gaetano, Maria Della Valle, Laura Zaccaro, Gaetano Malgieri, Biancamaria Farina, Luciano Pirone, Roberto Fattorusso, Farina, B., Pirone, L., D'Abrosca, G., Della Valle, M., Russo, L., Isernia, C., Sassano, M., Del Gatto, A., Di Gaetano, S., Zaccaro, L., Malgieri, G., Pedone, E. M., and Fattorusso, R.
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Lysis ,Protein Conformation ,Ligands ,Biochemistry ,Organic molecules ,Small Molecule Libraries ,Type ii diabetes ,Phospholipase D ,Humans ,Nuclear Magnetic Resonance, Biomolecular ,Binding Sites ,Chemistry ,Ligand ,Glucose transporter ,Insulin sensitivity ,Biological Transport ,General Medicine ,Peptide Fragments ,Molecular Docking Simulation ,Glucose ,Cellular Microenvironment ,Diabetes Mellitus, Type 2 ,Astrocytes ,Phosphoprotein ,Thermodynamics ,Molecular Medicine ,Insulin Resistance ,Apoptosis Regulatory Proteins ,Phospholipase D1 ,Protein Binding - Abstract
The overexpression of PED/PEA15, the phosphoprotein enriched in diabetes/phosphoprotein enriched in the astrocytes 15 protein (here referred simply to as PED), observed in some forms of type II diabetes, reduces the transport of insulin-stimulated glucose by binding to the phospholipase D1 (PLD1). The inhibition of the PED/PLD1 interaction was shown to restore basal glucose transport, indicating PED as a pharmacological target for the development of drugs capable of improving insulin sensitivity and glucose tolerance. We here report the identification and selection of PED ligands by means of NMR screening of a library of small organic molecules, NMR characterization of the PED/PLD1 interaction in lysates of cells expressing PLD1, and modulation of such interactions using BPH03, the best selected ligand. Overall, we complement the available literature data by providing detailed information on the structural determinants of the PED/PLD1 interaction in a cellular lysate environment and indicate BPH03 as a precious scaffold for the development of novel compounds that are able to modulate such interactions with possible therapeutic applications in type II diabetes.
- Published
- 2021
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