Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against autoimmune diseases

Abstract

SUMMARYTNF-α signaling plays a central role in the pathogenesis of various diseases, particularly autoimmune diseases. Screening of a library composed of FDA approved drugs led to the identification of Terfenadine and its active metabolite Fexofenadine as inhibitors of TNF-α signaling. Both Fexofenadine and Terfenadine inhibited TNF/NF-κB signaling in vitro and in vivo, and ameliorated disease symptoms in various autoimmune disease models, including TNF-α transgenic mice, collagen-induced arthritis, and inflammatory bowel disease. Subsequent studies identified cytosolic phospholipase A2 (cPLA2) as a novel target of Fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished Fexofenadine’s anti-TNF activity. Collectively, these findings not only provide new insights into the understanding of Fexofenadine action and underlying mechanism, but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly autoimmune diseases.

Penfluridol targets acid sphingomyelinase to inhibit TNF signaling and is therapeutic against inflammatory autoimmune diseases

“…Through first screening a FDA-approved small-molecule drug library containing 1046 drugs using NF-κB- bla THP1, secondary confirmation by NF-κB luciferase reporter assay, and third in vivo verification in hTNF-TG/NF-κB luc mutant mice, we identified penfluridol as one of five drugs that could inhibit TNFα-induced NF-κB activity [ 10 ]. Penfluridol is clinically used as an antipsychotic drug to treat various types of schizophrenia and its molecular structure is presented (Fig.…”

“…Fortunately, quick screening of FDA-approved on-market small-molecule drug library makes this possible. Through in vitro screening using NF-κB- bla THP-1 cell line and in vivo screening using human TNFα transgenic (hTNF-TG):NF-κB-Luc double mutant mice, penfluridol was identified as one of five small-molecule drugs that could inhibit TNFα-stimulated NF-κB activation [ 10 ]. Clinically, penfluridol, a first generation diphenylbutylpiperidine antipsychotic with a long half-life of 66 h, is a typical highly potent small-molecule drug used to treat chronic schizophrenia and related disorders [ 11 – 14 ], with treatment efficacy and risk of adverse events similar to chlorpromazine, a benchmark antipsychotic for schizophrenia.…”