Neoglycoconjugates Derived from Deoxynojirimycin as Possible Therapeutic Agents for Cystic Fibrosis Lung Disease, by Modulation of the Sphingolipid Metabolism

The identification and development of novel and more efficient anti-inflammatory drugs for management of Cystic Fibrosis (CF) airway disease remains a compelling need. Sphingolipids (SLs) play an important regulatory role in CF due to their function in pulmonary infections and inflammation. Given the emerging importance of SLs in much pathology, novel drugs are continuously developed to selectively target different enzymes involved in SL metabolism. Iminosugars disclose offer exciting and innovative opportunities for therapeutic agent discovery. Miglustat, the most popular iminosugar, has an anti-inflammatory effect in CF models through inhibiting non-lysosomal-β-glucosidase 2 (GBA2). A small library of neoglycoconjugates with an adamantane mojety (AMP-DNJ), characterized by differences in the length of the alkyl chain between the iminosugar and AMP, has been synthesized from the lead iminosugar deoxynojirimycin (DNJ) (Ardes-Guisot, 2011). This study was hence aimed to test the effect of these AMP-DNJ derivatives on the inflammatory response to P. aeruginosa in CF bronchial epithelial cells. Our original findings demonstrate that these AMP-DNJ derivatives reduce IL-8 mRNA expression in CF bronchial cells infected by P. aeruginosa at nanomolar concentrations. The selectivity towards β glucosidase seems to be modulated by variation of the length of the chain linking the iminosugar and AMP, which are key motifs for the therapeutic activity of these compounds. Our results further support the use of SL metabolism modulators for treating CF lung inflammation, thus providing useful hints on relevant targets and chemical structures that may be regarded as starting points for a drug discovery campaign.