A signalome screening approach in the autoinflammatory disease TNF Receptor Associated Periodic Syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

Todd, Ian and Negm, Ola H. and Reps, Jenna and Radford, Paul and Figueredo, Grazziela and McDermott, Elizabeth M. and Drewe, Elizabeth and Powell, Richard J. and Bainbridge, Susan and Hamed, Mohamed and Crouch, Sharon and Garibaldi, Jon and St-Gallay, Steve and Fairclough, Lucy C. and Tighe, Patrick J. (2017) A signalome screening approach in the autoinflammatory disease TNF Receptor Associated Periodic Syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing. Pharmacological Research . ISSN 1096-1186

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Abstract

TNF Receptor Associated Periodic Syndrome (TRAPS) is an autoinflammatory disease caused by mutations in TNF Receptor 1 (TNFR1). Current therapies for TRAPS are limited and do not target the pro-inflammatory signalling pathways that are central to the disease mechanism. Our aim was to identify drugs for repurposing as anti-inflammatories based on their ability to down-regulate molecules associated with inflammatory signalling pathways that are activated in TRAPS. This was achieved using rigorously optimised, high through- put cell culture and reverse phase protein microarray systems to screen compounds for their effects on the TRAPS-associated inflammatory signalome. 1360 approved, publically available, pharmacologically active substances were investigated for their effects on 40 signalling molecules associated with pro-inflammatory signalling pathways that are constitutively upregulated in TRAPS. The drugs were screened at four ten-fold concentrations on cell lines expressing both wild-type (WT) TNFR1 and TRAPS-associated C33Y mutant TNFR1, or WT TNFR1 alone; signalling molecule levels were then determined in cell lysates by the reverse phase protein microarray. A novel mathematical methodology was developed to rank the compounds for their ability to reduce the expression of signalling molecules in the C33Y-TNFR1 transfectants towards the level seen in the WT-TNFR1 transfectants. Seven high-ranking drugs were selected and tested by RPPA for effects on the same 40 signalling molecules in lysates of peripheral blood mononuclear cells (PBMCs) from C33Y-TRAPS patients compared to PBMCs from normal controls. The fluoroquinolone antibiotic lomefloxacin, as well as others from this class of compounds, showed the most significant effects on multiple pro-inflammatory signalling pathways that are constitutively activated in TRAPS; lomefloxacin dose-dependently significantly reduced expression of 7/40 signalling molecules across the Jak/Stat, MAPK, NF-kB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.

Item Type: Article
Keywords: Drug repurposing, Reverse-phase protein micro-array, Signalome, TNF receptor associated periodic syndrome, Fluoroquinolone, Anti-inflammatory
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Computer Science
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: 10.1016/j.phrs.2017.08.012
Depositing User: Eprints, Support
Date Deposited: 26 Sep 2017 10:12
Last Modified: 13 Oct 2017 19:25
URI: http://eprints.nottingham.ac.uk/id/eprint/46737

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