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

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator associated to 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.

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

“…Modulating the production of S1P has the potential to affect a wide range of diseases including cancer, , sickle cell disease, , atherosclerosis, , asthma, , diabetes, and fibrosis . Initial drug discovery efforts have yielded potent SphK1 inhibitors, a process that was aided by the availability of a SphK1 crystal structure. − However, such inhibitors have proven more elusive for SphK2, for which no crystal structure currently exists. Instead, inhibitor design has largely focused on homology modeling and developing ATP-competitive inhibitors.…”