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

Lysophospholipids are a class of simple phospholipids that shows their biological effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is one of the most studied lysophospholipid having wide role in various pathophysiological and cellular events, via signalling through five distinct GPCR subtypes, S1P receptors 1-5 (S1PR1-S1PR5).The importance of S1P pathway in drug targets have gained attention significantly after the approval of three S1PR modulators, fngolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS). S1P, a signal transmitter, is converted to S1P by phosphorylation of Sphingosine kinase (SK1 or SK2) enzymes. S1P acts as an extracellular and intracellular ligand for receptors, S1PR1-5. The SK1/S1P axis and the connected S1PR1-5 plays important roles in many cellular events involving cell signalling, the cell survival/apoptosis, the production of pro-inflammatory cytokine responses, maintaining vascular integrity etc. Further sphingolipids, glycosphingolipids and ceramides acts as receptor/co-receptor for viral entry & downstream signalling, formation of lipid raft-mediated microdomain, viral induced apoptosis. S1P receptor modulator fingolimod shows antiviral activity against human immunodeficiency virus. Currently, the clinical trials of ozanimod (a sphingosine receptor modulator), and opaganib (a SK2inhibitor) are being conducted for treatment of COVID-19. In this review we explored the different roles of sphingolipids, S1P, S1PR, SK in viral infections including a special focus on SARS-CoV2. 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 receptors.