Exploring SK/S1P/S1PR pathway as a target for antiviral drug development

Abstract

Sphingosine-1-phosphate (S1P) is a signal transmitter. The lipid sphingosine is converted to S1P by catalysis of Sphingosine kinase enzymes (SK1 or SK2). S1P acts extracellularly as a receptor ligand. The SK1/S1P axis plays important roles in cell signalling, the cell death/survival, the production of a pro-inflammatory response, and maintaining vascular integrity. There are five subtypes of S1P receptor known as S1P1, S1P2, S1P3, SP4, and S1P5. Glycosphingolipids promote viral entry. The drug molecules targeting the SK1/S1P axis such as fingolimod, ozanimod, and ponesimod are used for treatment of multiple sclerosis. S1P receptor modulator drug fingolimod shows antiviral activity against human immunodeficiency virus. Currently, the clinical trials of ozanimod (a sphingosine receptor modulator), and opaganib (a SK2 inhibitor) are being conducted for treatment of COVID-19. It is worth to target SK/S1P pathway to develop antiviral drugs, by repurposing existing inhibitors/modulators, and designing new specific inhibitors of SK1, SK2, and SP receptor.