Replication of Equine arteritis virus is efficiently suppressed by purine and pyrimidine biosynthesis inhibitors

jose-carlos Valle-Casuso; Delphine Gaudaire; Lydie Martin-Faivre; anthony madeline; Patrick Dallemagne; Stephane Pronost; Helene Munier-Lehmann; Stephan Zientara; Pierre-Olivier Vidalain; Aymeric Hans

The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.10.035402 doi: bioRxiv preprint vaccination, reduce viral spreading in equine structures and contain EAV outbreaks. This is supported 86 by a recent study showing that a global strategy based on vaccination combined with drug therapies 87 enhances protection against foot-and-mouth disease 10 . In our study, we have developed a high-88 throughput cell-viability assay based on infected equine dermal cells. Then, we took advantage of this 89 new assay to explore the potential of broad-spectrum antivirals ( replication through multiple direct and indirect mechanisms. In particular, ribavirin inhibits inosine 5'-103 monophosphate dehydrogenase (IMPDH), a key enzyme catalyzing the first committed and rate-104 limiting step in the de novo synthesis of guanine nucleotides. As such, IMPDH inhibition interferes with 105 the production of GTP that is necessary for the synthesis of viral RNA molecules 22 , but other 106 mechanisms have been reported such as the direct inhibition of viral polymerases or the lethal 107 mutagenesis of viral genomes 23,24 . Besides ribavirin, we also tested two newly designed BSA that 108 target the pyrimidine biosynthesis pathway, namely GAC50 and IPPA17-A04. These two molecules 109 are inhibitors of dihydroorotate dehydrogenase (DHODH), the fourth and rate-limiting enzyme of the 110 de novo pyrimidine biosynthesis pathway, and were shown to impair the replication of many different 111 positive-strand and negative-strand RNA viruses [25] [26] [27] . In this study, we have shown, for the first time, 112 that both ribavirin and pyrimidine biosynthesis inhibitors inhibit EAV in equine dermal cell cultures. 113 114 115 author/funder. All rights reserved. No reuse allowed without permission.