Lifecycle modelling systems support inosine monophosphate dehydrogenase (IMPDH) as a pro-viral factor and antiviral target for New World arenaviruses

Lujo virus (LUJV), a highly pathogenic arenavirus, was first identified in 2008 in Zambia. To aid the identification of effective therapeutics for LUJV, we developed a recombinant reporter virus system, confirming reporter LUJV comparability with wild-type virus and its utility in high-throughput antiviral screening assays. Using this system, we evaluated compounds with known and unknown efficacy against related arenaviruses, with the aim of identifying LUJV-specific and potential new pan-arenavirus antivirals. We identified six compounds demonstrating robust anti-LUJV activity, including several compounds with previously reported activity against other arenaviruses. These data provide critical evidence for developing broad-spectrum antivirals against high-consequence arenaviruses.

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Screening and Identification of Lujo Virus Inhibitors Using a Recombinant Reporter Virus Platform

Welch

Spengler

Genzer

et al. 2021

“…Consistently, merimepodib (MMPD, VX-497), a potent inhibitor of IMPDH, had an antiviral activity against JUNV, as evidenced by a reduction in viral production [130]. Thereafter, experiments using a JUNV minireplicon assay further showed that a noncompetitive inhibitor of IMPDH reduced viral RNA synthesis and that siRNA-mediated knockdown of human IMPDH2 markedly affected minigenome-containing VLP production, thus suggesting a key role of IMPDH2 in viral RNA synthesis [131].…”

Section: Junv Z Protein-binding Partners Related To the Cellular Ener...mentioning

confidence: 90%

“…Simultaneously, several minigenome (MG) (also known as minireplicon) reverse genetics systems have been designed for JUNV and have been widely used to understand the molecular mechanisms underlying the viral replication process [13,131,233,235,236]. These platforms specifically allow the modeling of viral RNA synthesis, in contrast to the previously described infectious recombinant JUNV, oriented to the analysis of the whole virus life cycle.…”

Section: Alternative Systems To Evaluate Junv Replication Assembly An...mentioning

confidence: 99%

The Virus–Host Interplay in Junín Mammarenavirus Infection

Gallo

López

Loureiro

2022

Junín virus (JUNV) belongs to the Arenaviridae family and is the causative agent of Argentine hemorrhagic fever (AHF), a severe human disease endemic to agricultural areas in Argentina. At this moment, there are no effective antiviral therapeutics to battle pathogenic arenaviruses. Cumulative reports from recent years have widely provided information on cellular factors playing key roles during JUNV infection. In this review, we summarize research on host molecular determinants that intervene in the different stages of the viral life cycle: viral entry, replication, assembly and budding. Alongside, we describe JUNV tight interplay with the innate immune system. We also review the development of different reverse genetics systems and their use as tools to study JUNV biology and its close teamwork with the host. Elucidating relevant interactions of the virus with the host cell machinery is highly necessary to better understand the mechanistic basis beyond virus multiplication, disease pathogenesis and viral subversion of the immune response. Altogether, this knowledge becomes essential for identifying potential targets for the rational design of novel antiviral treatments to combat JUNV as well as other pathogenic arenaviruses.

“…In A549 cells Mycophenolic acid exhibited weak inhibitory activity based on the SI-MTT and SI-XTT ( Table 6 ). AVN-944 has been described to have anticancer properties as well as broad spectrum antiviral activity against various viruses ( Table 7 ) [ 17 , 37 , 50 , 51 ]. We identified AVN-944 as a potent post-treatment inhibitor of ZIKV based on SI-MTT and SI-XTT ( Table 1 ), a potent pre-treatment inhibitor based on SI-MTT and a moderate inhibitor based on SI-XTT ( Table 2 ), and a moderate co-treatment inhibitor based on SI-MTT and SI-XTT ( Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Inhibitors of ZIKV Replication

Vasquez

Park

Ávila‐Pérez

et al. 2020

Zika virus (ZIKV) was identified in 1947 in the Zika forest of Uganda and it has emerged recently as a global health threat, with recurring outbreaks and its associations with congenital microcephaly through maternal fetal transmission and Guillain-Barré syndrome. Currently, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines or antivirals to treat ZIKV infections, which underscores an urgent medical need for the development of disease intervention strategies to treat ZIKV infection and associated disease. Drug repurposing offers various advantages over developing an entirely new drug by significantly reducing the timeline and resources required to advance a candidate antiviral into the clinic. Screening the ReFRAME library, we identified ten compounds with antiviral activity against the prototypic mammarenavirus lymphocytic choriomeningitis virus (LCMV). Moreover, we showed the ability of these ten compounds to inhibit influenza A and B virus infections, supporting their broad-spectrum antiviral activity. In this study, we further evaluated the broad-spectrum antiviral activity of the ten identified compounds by testing their activity against ZIKV. Among the ten compounds, Azaribine (SI-MTT = 146.29), AVN-944 (SI-MTT = 278.16), and Brequinar (SI-MTT = 157.42) showed potent anti-ZIKV activity in post-treatment therapeutic conditions. We also observed potent anti-ZIKV activity for Mycophenolate mofetil (SI-MTT = 20.51), Mycophenolic acid (SI-MTT = 36.33), and AVN-944 (SI-MTT = 24.51) in pre-treatment prophylactic conditions and potent co-treatment inhibitory activity for Obatoclax (SI-MTT = 60.58), Azaribine (SI-MTT = 91.51), and Mycophenolate mofetil (SI-MTT = 73.26) in co-treatment conditions. Importantly, the inhibitory effect of these compounds was strain independent, as they similarly inhibited ZIKV strains from both African and Asian/American lineages. Our results support the broad-spectrum antiviral activity of these ten compounds and suggest their use for the development of antiviral treatment options of ZIKV infection.