Antiviral activity of A771726, the active metabolite of leflunomide, against Junín virus

Abstract

The aim of this study was to investigate the effect of A771726, the active metabolite of leflunomide, (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad against the infection with Junín virus (JUNV), agent of Argentine hemorrhagic fever (AHF). The treatment with non-cytotoxic concentrations of A771726 of Vero and A549 cells infected with JUNV inhibited virus replication in a dose-dependent manner, as determined by virus yield reduction assay. The antiviral effectiveness of A771726 was not importantly affected by the multiplicity of infection and the virus strain. Moreover, the combination of A771726 and ribavirin had a significantly more potent antiviral activity than each single drug treatment. Mechanistic studies showed that the main action of A771726 is exerted before 6 h of JUNV infection. Accordingly, inhibition of viral RNA synthesis was detected in treated infected cells by real time RT-PCR. The exogenous addition of uridine or orotic acid produced a partial reversal of the inhibitory effect of A771726 on infective virus production whereas a total reversion was detected on JUNV RNA synthesis, probably by restoration of the enzymatic activity of dihydroorotate dehydrogenase (DHODH) and the intracellular pyrimidine pools. In conclusion, these results suggest that the antiviral target would be viral RNA synthesis through pyrimidine depletion, but any other effect of the compound on JUNV infection cannot be excluded. This study opens the possibility of the therapeutic application of a wide spectrum host-targeted compound alone or in combination with ribavirin to combat AHF as well as other human pathogenic arenaviruses.

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…Reducing pyrimidine pool, teriflunomide can inhibit the replication of Junìn virus, the agent of Argentine hemorrhagic fever and an enveloped negative-sense ssRNA arenavirus, in a dose-dependent manner. The combination with ribavirin appeared to have a stronger anti-viral activity than monotherapy [114].…”

Dihydroorotate dehydrogenase inhibitors in SARS‐CoV‐2 infection

“…DHODH inhibitors were already demonstrated to have antiviral activity against positive and negative ‐sense RNA and DNA viruses, 13,14 namely foot‐and‐mouth disease virus, 24 Junín virus, 25 rotavirus 26 , and particularly against Ebola 15 . While the salvage pathway, that recycles products of DNA/RNA degradation and from nutrients, is usually sufficient to support nonrapidly proliferative cells, viruses ‘kidnap’ the de novo pyrimidine synthesis pathway of the infected‐host cells to sustain their rapid replication.…”

Multi-ancestry omic Mendelian randomization revealing putative drug targets of COVID-19 severity

“…Leflunomide is an immune suppressive drug used for autoimmune diseases, such as rheumatoid arthritis (34). It also showed antiviral effect against a wide range of DNA and RNA viruses, such as herpes simplex virus (35), human cytomegalovirus (36)(37), polyoma BK virus (38)(39), Junín virus (40), influenza A virus, Zika virus and Ebola virus. Recent studies also suggested its anti-SARS-CoV-2 effect (18)(19).…”