OBJECTIVES

: Systemic Onset Juvenile Idiopathic Arthritis (sJIA) is the rarest form of juvenile idiopathic arthritis (JIA) associated with dysregulation of innate immune system. IL-1 and IL-6 play a major role in the pathogenesis of sJIA. It is characterized by fever, lymphadenopathy, arthritis, rash, and serositis. Severe complications involving growth delay, bone and cartilage erosion with functional handicap, and a risk of osteopaenia continue to be a major concern. This study aims to identify novel potential druggable targets and determine the off-label therapeutic possibilities for sJIA.

METHODS

: Differentially Expressed Genes (DEGs) were retrieved from GSE103500 of GEO database through GEO2R. The Protein Protein Interactions (PPI) of existing genes from NCBI and DEGs obtained from GEO2R were studied using STRING. Genes having direct interaction with the known genes were selected. Drugs for the selected targets were gathered from Drug Repurposing Hub, NIH LINCS project. Drug similarity search for the standards were performed in DrugBank. Standards and similar drugs were docked using Schrodinger Glide tool with the target obtained from PDB. Pharmacokinetic and physiochemical properties were predicted using Qikprop analysis.

RESULTS

: A total of 429 genes (P<0.05, logFC>2) including both up and down regulated genes were obtained. PPI analysis revealed membrane metallo-endopeptidase (MME) with significant interactions which was an upregulated gene. Sacubitril and racecadotril having 6 and 7 similar drugs respectively were obtained as standard inhibitors for MME. Sacubitril, sacubitrilat, Methylphenidate and dexamethylphenidate were found to have better docking score and obeyed Lipinski’s rule of five.

CONCLUSIONS

: Exploring key pathogenic factors and drug re-appraisal would circumvent initial stages of drug discovery. Therefore, these hypothesis serve as an excellent basis for further invitro and invivo studies suggesting that Sacubitril, Sacubitrilat, Methylphenidate and Dexamethylphenidate drugs could be repurposed for sJIA.