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A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing

Figueredo, Grazziela; Todd, Ian; Negm, Ola H.; Reps, Jenna; Radford, Paul; Figueredo, Grazziela P.; McDermott, Elizabeth M.; Drewe, Elizabeth; Powell, Richard J.; Bainbridge, Susan; Hamed, Mohamed; Crouch, Sharon; Garibaldi, Jon; St-Gallay, Steve; Fairclough, Lucy C.; Tighe, Patrick J.

Authors

Grazziela Figueredo

Ian Todd

Ola H. Negm

Paul Radford

Grazziela P. Figueredo

Elizabeth M. McDermott

Elizabeth Drewe

Richard J. Powell

Sharon Crouch

Jon Garibaldi

Steve St-Gallay

Lucy C. Fairclough

Patrick J. Tighe



Abstract

© 2017 Elsevier Ltd 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 optimized, 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 10-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-κB and PI3K/AKT pathways. This study demonstrates the power of signalome screening for identifying candidates for drug repurposing.

Journal Article Type Article
Publication Date 2017-11
Journal Pharmacological Research
Print ISSN 1043-6618
Electronic ISSN 1096-1186
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 125
Pages 188-200
APA6 Citation Figueredo, G., Todd, I., Negm, O. H., Reps, J., Radford, P., Figueredo, G. P., …Tighe, P. 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, 125, 188-200. https://doi.org/10.1016/j.phrs.2017.08.012
DOI https://doi.org/10.1016/j.phrs.2017.08.012
Keywords Drug repurposing, Reverse-phase protein micro-array, Signalome, TNF receptor associated periodic syndrome,
Fluoroquinolone, Anti-inflammatory
Publisher URL https://www.sciencedirect.com/science/article/pii/S1043661817305613?via%3Dihub
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0
Additional Information This article is maintained by: Elsevier; Article Title: A signalome screening approach in the autoinflammatory disease TNF receptor associated periodic syndrome (TRAPS) highlights the anti-inflammatory properties of drugs for repurposing; Journal Title: Pharmacological Research; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.phrs.2017.08.012; Content Type: article; Copyright: © 2017 Elsevier Ltd. All rights reserved.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by-nc-nd/4.0





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