Farina Biancamaria, Pirone Luciano, D'Abrosca Gianluca, Della Valle Maria, Russo Luigi, Isernia Carla, Sassano Marica, Del Gatto Annarita, Di Gaetano Sonia, Zaccaro Laura, Malgieri Gaetano, Pedone Emilia M, Fattorusso Roberto
Istituto di Biostrutture e Bioimmagini, CNR, via Mezzocannone 16, 80134 Napoli, Italy.
Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania─L. Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy.
ACS Chem Biol. 2021 Dec 17;16(12):2798-2807. doi: 10.1021/acschembio.1c00688. Epub 2021 Nov 26.
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.
在某些II型糖尿病形式中观察到富含糖尿病的磷蛋白/富含星形胶质细胞的磷蛋白15（PED/PEA15，此处简称为PED）的过表达，它通过与磷脂酶D1（PLD1）结合来减少胰岛素刺激的葡萄糖转运。PED/PLD1相互作用的抑制被证明可恢复基础葡萄糖转运，这表明PED是开发能够改善胰岛素敏感性和葡萄糖耐量的药物的药理学靶点。我们在此报告通过对小分子有机化合物库进行核磁共振筛选来鉴定和选择PED配体，对表达PLD1的细胞裂解物中PED/PLD1相互作用进行核磁共振表征，并使用最佳选择的配体BPH03调节这种相互作用。总体而言，我们通过提供细胞裂解物环境中PED/PLD1相互作用的结构决定因素的详细信息来补充现有文献数据，并表明BPH03是开发新型化合物的宝贵支架，这些化合物能够调节这种相互作用，并可能在II型糖尿病中具有治疗应用。
