Original Chemical Series of Pyrimidine Biosynthesis Inhibitors That Boost the Antiviral Interferon Response.

Autor:	Lucas-Hourani M; Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR3569, Paris, France., Dauzonne D; Institut Curie, Centre de Recherche, CNRS UMR3666, INSERM U1143, Paris, France., Munier-Lehmann H; Unité de Chimie et Biocatalyse, Institut Pasteur, CNRS UMR3523 Paris, France., Khiar S; Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR3569, Paris, France., Nisole S; IRIM CNRS UMR9004, Université de Montpellier, Montpellier, France., Dairou J; Equipe Chimie Bio-inorganique des Dérivés Soufrés et Pharmacochimie, Université Paris Descartes, CNRS UMR8601, Paris, France., Helynck O; Unité de Chimie et Biocatalyse, Institut Pasteur, CNRS UMR3523 Paris, France., Afonso PV; Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie, Institut Pasteur, CNRS UMR3569, Paris, France., Tangy F; Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR3569, Paris, France ftangy@pasteur.fr pierre-olivier.vidalain@parisdescartes.fr., Vidalain PO; Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR3569, Paris, France ftangy@pasteur.fr pierre-olivier.vidalain@parisdescartes.fr.; Equipe Chimie & Biologie, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes, CNRS UMR8601, Paris, France.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2017 Sep 22; Vol. 61 (10). Date of Electronic Publication: 2017 Sep 22 (Print Publication: 2017).
DOI:	10.1128/AAC.00383-17
Abstrakt:	De novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. Here, we identified an original series of 3-(1 H -indol-3-yl)-2,3-dihydro-4 H -furo[3,2- c ]chromen-4-one derivatives as a new class of pyrimidine biosynthesis inhibitors formed by two edge-fused polycyclic moieties. We show that identified compounds exhibit broad-spectrum antiviral activity and immunostimulatory properties, in line with recent reports linking de novo pyrimidine biosynthesis with innate defense mechanisms against viruses. Most importantly, we establish that pyrimidine deprivation can amplify the production of both type I and type III interferons by cells stimulated with retinoic acid-inducible gene 1 (RIG-I) ligands. Altogether, our results further expand the current panel of pyrimidine biosynthesis inhibitors and illustrate how the production of antiviral interferons is tightly coupled to this metabolic pathway. Functional and structural similarities between this new chemical series and dicoumarol, which was reported before to inhibit pyrimidine biosynthesis at the dihydroorotate dehydrogenase (DHODH) step, are discussed. (Copyright © 2017 Lucas-Hourani et al.)
Databáze:	MEDLINE
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