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

Abstract

26RNA viruses are responsible for a large variety of animal infections. Equine Arteritis Virus (EAV) is a 27 positive single-stranded RNA virus member of the family Arteriviridae from the order Nidovirales like 28 the Coronaviridae. EAV causes respiratory and reproductive diseases in equids. Although two 29 vaccines are available, the vaccination coverage of the equine population is largely insufficient to 30 prevent new EAV outbreaks around the world. In this study, we present a high-throughput in vitro 31 assay suitable for testing candidate antiviral molecules on equine dermal cells infected by EAV. Using 32 this assay, we identified three molecules that impair EAV infection in equine cells: the broad-spectrum 33 antiviral and nucleoside analog ribavirin, and two compounds previously described as inhibitors of 34 dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. 35 These molecules effectively suppressed cytopathic effects associated to EAV infection, and strongly 36 inhibited viral replication and production of infectious particles. Since ribavirin is already approved in 37 human and small animal, and that several DHODH inhibitors are in advanced clinical trials, our results 38 open new perspectives for the management of EAV outbreaks. 39 40 41 Keywords: Antiviral activity, equine arteritis virus, dihydroorotate dehydrogenase, pyrimidine 42 biosynthesis inhibitor, ribavirin. 43 44 45 46 47 48

Regulation of the pyrimidine biosynthetic pathway by lysine acetylation of E. coliOPRTase

“…Furthermore, the upregulation of some enzymes in this pathway indicates a poor prognosis in cancer patients, hence these genes are attractive anticancer drugs to inhibit proliferation and metastasis [16–19]. Likewise, viral replication relies on the host to supply nucleotides, thus the enzymes in this pathway are targets for antiviral treatments [20–23]. Moreover, the inhibition of pyrimidine biosynthesis enzymes is employed for the treatment of microorganism and parasite infections [24–27].…”

“…Likewise, viral replication relies on the host to supply nucleotides, thus the enzymes in this pathway are targets for antiviral treatments [20][21][22][23]. Moreover, the inhibition of pyrimidine biosynthesis enzymes is employed for the treatment of microorganism and parasite infections [24][25][26][27].…”

Review of two viral agents of economic importance to the equine industry (equine herpesvirus‐1, and equine arteritis virus)

“…Recent studies carried out byValle-Casuso et al (2020) presented a high-throughput in vitro assay suitable for testing candidate antiviral molecules in equine dermal cells infected by EAV.The authors identified three molecules that impair EAV infection in equine cells: the broad-spectrum antiviral and nucleoside analogue ribavirin, and two compounds previously described as inhibitors of dihydroorotate dehydrogenase (DHODH), the fourth enzyme of the pyrimidine biosynthesis pathway. These molecules effectively suppressed cytopathic effects associated with EAV infection, and strongly inhibited viral replication and production of infectious particles.…”