Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator associated with diverse homeostatic and signaling roles. Enhanced biosynthesis of SIP, mediated by the sphingosine kinase isozymes (SK1 and SK2), is implicated in several pathophysiological conditions and diseases, including skeletal muscle fibrosis, inflammation, multiple sclerosis, and cancer. Therefore, therapeutic approaches that control S1P production have focused on the development of SK1/2 inhibitors. In this framework, we designed a series of natural monosaccharide-based compounds to enhance anchoring of the known SK1 inhibitor PF-543 at the polar head of the J-shaped substrate-binding channel. Herein, we describe the structure-based design and synthesis of new glycan-containing PF-543 analogues and we demonstrate their efficiency in a TGF beta 1-induced pro-fibrotic assay.
Glycans Meet Sphingolipids: Structure-Based Design of Glycan Containing Analogues of a Sphingosine Kinase Inhibitor / A. Papakyriakou, F. Cencetti, E. Puliti, L. Morelli, J. Tricomi, P. Bruni, F. Compostella, B. Richichi. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - 11:5(2020), pp. 913-920.
|Titolo:||Glycans Meet Sphingolipids: Structure-Based Design of Glycan Containing Analogues of a Sphingosine Kinase Inhibitor|
COMPOSTELLA, FEDERICA (Penultimo) (Corresponding)
|Parole Chiave:||Sphingosine 1-phosphate; skeletal muscle fibrosis; glycan derivatives; molecular modeling; sphingosine kinase 1|
|Settore Scientifico Disciplinare:||Settore BIO/10 - Biochimica|
|Data di pubblicazione:||2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1021/acsmedchemlett.9b00665|
|Appare nelle tipologie:||01 - Articolo su periodico|