Inhibition of Pyrimidine Biosynthesis Pathway Suppresses Viral Growth through Innate Immunity

• DOI: 10.1371/journal.ppat.1003678
• Publication Date: 2013-10-03T21:10:28Z
• Authors: Marianne Lucas-Ho...; Daniel Dauzonne; Pierre Jorda; Gaëlle Cousin; Alexandru Lupan; Olivier Helynck; Grégory Caignard; Geneviève Janvier; Gwénaëlle André-L...; Samira Khiar; Nicolas Escriou; Philippe Desprès; Yves Jacob; Hélène Munier-Leh...; Frédéric Tangy; Pierre-Olivier Vi...
• Keywords: Pyrimidine metabolism; IRF1; Transcription

Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. Here, we established a cell-based reporter assay identify compounds stimulating expression interferon-inducible genes. DD264 was selected out 41,353 both its immuno-stimulatory and properties. While searching mode action, identified as inhibitor pyrimidine biosynthesis pathway. This metabolic pathway recently prime target broad-spectrum molecules, but our data unraveled yet unsuspected link with immunity. Indeed, showed that or brequinar, well-known pathway, enhanced genes in human cells. Furthermore, activity brequinar found strictly dependent on cellular gene transcription, nuclear export machinery, required IRF1 transcription factor. In conclusion, property inhibitors not direct consequence deprivation virus rather involves induction immune response.