Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator associated with diverse homeostatic and signaling roles. Enhanced biosynthesis of S1P, 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 TGFβ1- induced pro-fibrotic assay.

Glycans Meet Sphingolipids: Structure-Based Design of Glycan Containing Analogues of a Sphingosine Kinase Inhibitor / Athanasios Papakyriakou, Francesca Cencetti, Elisa Puliti, Laura Morelli, Jacopo Tricomi, Paola Bruni, Federica Compostella, Barbara Richichi. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - ELETTRONICO. - 11:(2020), pp. 913-920. [10.1021/acsmedchemlett.9b00665]

Glycans Meet Sphingolipids: Structure-Based Design of Glycan Containing Analogues of a Sphingosine Kinase Inhibitor

Francesca Cencetti;Elisa Puliti;Jacopo Tricomi;Paola Bruni;Federica Compostella
;
Barbara Richichi
2020

Abstract

Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator associated with diverse homeostatic and signaling roles. Enhanced biosynthesis of S1P, 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 TGFβ1- induced pro-fibrotic assay.
2020
11
913
920
Athanasios Papakyriakou, Francesca Cencetti, Elisa Puliti, Laura Morelli, Jacopo Tricomi, Paola Bruni, Federica Compostella, Barbara Richichi
File in questo prodotto:
File Dimensione Formato  
ACSMedChemLEtt_2020.pdf

Accesso chiuso

Descrizione: PDf editoriale
Tipologia: Pdf editoriale (Version of record)
Licenza: Creative commons
Dimensione 6.73 MB
Formato Adobe PDF
6.73 MB Adobe PDF   Richiedi una copia

I documenti in FLORE sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1194488
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 3
  • ???jsp.display-item.citation.isi??? 2
social impact