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

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2020 May 22

PMID 32435405

Citations 1

Authors

Athanasios Papakyriakou

Francesca Cencetti

Elisa Puliti

Laura Morelli

Jacopo Tricomi

Paola Bruni

Federica Compostella

Barbara Richichi

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Sphingosine Kinase 2 Inhibitors: Rigid Aliphatic Tail Derivatives Deliver Potent and Selective Analogues.

Pashikanti S, Foster D, Kharel Y, Brown A, Bevan D, Lynch K ACS Bio Med Chem Au. 2022; 2(5):469-489.

PMID: 36281302 PMC: 9585524. DOI: 10.1021/acsbiomedchemau.2c00017.

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