| DOI | Trouver le DOI : https://doi.org/10.1016/j.chembiol.2018.10.002 |
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| Auteur | Rechercher : Ivarsson, Mattias E.; Rechercher : Durantie, Estelle; Rechercher : Huberli, Corina; Rechercher : Huwiler, Samuel; Rechercher : Hegde, Chrismita; Rechercher : Friedman, Jillian; Rechercher : Altamura, Fernando; Rechercher : Lu, Jun; Rechercher : Verdu, Elena F.; Rechercher : Bercik, Premysl; Rechercher : Logan, Susan M.1; Rechercher : Chen, Wangxue1; Rechercher : Leroux, Jean-Christophe; Rechercher : Castagner, Bastien |
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| Affiliation | - Conseil national de recherches du Canada. Thérapeutique en santé humaine
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| Format | Texte, Article |
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| Sujet | Clostridium difficile; bacterial toxins; small-molecule drug; allosteric modulator; inositol phosphate; non-antibiotic strategy |
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| Résumé | Clostridium difficile causes increasing numbers of life-threatening intestinal infections. Symptoms associated with C. difficile infection (CDI) are mediated by secreted protein toxins, whose virulence is modulated by intracellular auto-proteolysis following allosteric activation of their protease domains by inositol hexakisphosphate (IP6). Here, we explore the possibility of inactivating the C. difficile toxin B (TcdB) by triggering its auto-proteolysis in the gut lumen prior to cell uptake using gain-of-function small molecules. We anticipated that high calcium concentrations typically found in the gut would strongly chelate IP6, precluding it from pre-emptively inducing toxin auto-proteolysis if administered exogenously. We therefore designed IP6 analogs with reduced susceptibility to complexation by calcium, which maintained allosteric activity at physiological calcium concentrations. We found that oral administration of IP6 analogs attenuated inflammation and promoted survival in mouse models of CDI. Our data provide impetus to further develop small-molecule allosteric triggers of toxin auto-proteolysis as a therapeutic strategy. |
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| Date de publication | 2018-10-25 |
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| Maison d’édition | Elsevier |
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| Dans | |
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| Langue | anglais |
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| Publications évaluées par des pairs | Oui |
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| Numéro NPARC | 23004552 |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | 2dc17b8c-a15b-4d42-b919-63434ca62dbd |
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| Enregistrement créé | 2018-11-20 |
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| Enregistrement modifié | 2020-03-16 |
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