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

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.