Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1 |
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| Authors: | Dr Nassim Mahtal Clémence Brewee Sylvain Pichard Dr Orane Visvikis Dr Jean‐Christophe Cintrat Dr Julien Barbier Dr Emmanuel Lemichez Prof Daniel Gillet |
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| Affiliation: | 1. Service d'Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, Gif/Yvette, France;2. Service de Chimie Bio-organique et Marquage (SCBM), CEA, Université Paris-Saclay, Gif/Yvette, France;3. INSERM U1065, Equipe Labellisée Ligue Contre le Cancer, Centre Méditerranéen de Médecine Moléculaire (C3M), Université de Nice, Sophia-Antipolis, Nice, France |
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| Abstract: | Cytotoxic necrotizing factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra‐intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work we developed a fluorescent cell‐based immunoassay to screen for inhibitors of CNF1‐induced Rac1 degradation among 1120 mostly approved drugs. Eleven compounds were found to prevent CNF1‐induced Rac1 degradation, and five also showed a protective effect against CNF1‐induced multinucleation. Finally, lasalocid, monensin, bepridil, and amodiaquine protected cells from both diphtheria toxin and CNF1 challenges. These data highlight the potential for drug repurposing to fight several bacterial infections and Rac1‐based diseases. |
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| Keywords: | CNF1 drug discovery inhibitors Rac1 screening |
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