Abstract
ABSTRACTDe novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. Here, we identified an original series of 3-(1H-indol-3-yl)-2,3-dihydro-4H-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.
Highlights
De novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes
The antiviral activity of pyrimidine biosynthesis inhibitors was found to be strictly dependent on cellular gene transcription and nuclear export machinery and required interferon regulatory factor 1 (IRF1), a key transcription factor driving the expression of antiviral genes, including interferon-stimulated genes (ISGs) [8]
It was shown that pyrimidine biosynthesis inhibitors could increase the expression of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic sensor inducing the expression of innate immunity genes and IFNs in response to RNA virus infections [16]
Summary
De novo pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. It was shown that pyrimidine biosynthesis inhibitors could increase the expression of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic sensor inducing the expression of innate immunity genes and IFNs in response to RNA virus infections [16] These different reports support a key role of the innate immune response in the antiviral activity of compounds inhibiting the de novo pyrimidine biosynthesis pathway. A functional study of this chemical series led us to show for the first time that in cells transfected with RIG-I ligands mimicking a viral infection, the production of type I interferon (IFN-I) and IFN-III is strongly boosted when de novo pyrimidine biosynthesis is blocked This new observation unravels a mechanism by which cells modulate their communication with neighboring cells as a function of their metabolic status
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