Inhibition of Arenavirus by A3, a Pyrimidine Biosynthesis Inhibitor

Abstract

dArenaviruses merit significant interest as important human pathogens, since several of them cause severe hemorrhagic fever disease that is associated with high morbidity and significant mortality. Currently, there are no FDA-licensed arenavirus vaccines available, and current antiarenaviral therapy is limited to an off-labeled use of the nucleoside analog ribavirin, which has limited prophylactic efficacy. The pyrimidine biosynthesis inhibitor A3, which was identified in a high-throughput screen for compounds that blocked influenza virus replication, exhibits a broad-spectrum antiviral activity against negative-and positive-sense RNA viruses, retroviruses, and DNA viruses. In this study, we evaluated the antiviral activity of A3 against representative Old World (lymphocytic choriomeningitis virus) and New World (Junin virus) arenaviruses in rodent, monkey, and human cell lines. We show that A3 is significantly more efficient than ribavirin in controlling arenavirus multiplication and that the A3 inhibitory effect is in part due to its ability to interfere with viral RNA replication and transcription. We document an additive antiarenavirus effect of A3 and ribavirin, supporting the potential combination therapy of ribavirin and pyrimidine biosynthesis inhibitors for the treatment of arenavirus infections.

Replication-competent influenza A viruses expressing a red fluorescent protein

“…Antiviral-mediated inhibition of PR8 and pH1N1 WT and mCherry viruses was evaluated as previously described (Bauman et al, 2013) using 2- and 3-fold serial dilutions of ribavirin (Sidwell et al, 1972) or A3 (Hoffmann et al, 2011, Ortiz-Riano et al, 2014) at a starting concentration of 100 μM and 20 μM, respectively. Sigmoidal dose-response curves were generated (Graphpad Prism) to calculate IC 50 values.…”

An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation

“…Despite the increasing amount of research aimed at identifying antiviral agents against EV71, no direct acting anti-EV71 drugs are currently available in the clinic to combat EV71 infections . Some compounds have been reported to have inhibitory effects against EV71, including pleconaril, CsA, BPR0Z and GPP3-1 (both target virus entry) (Shang et al, 2013;Zhang et al, 2012;Shia et al, 2002;De Colibus et al, 2014;Qing et al, 2014;Ortiz-Riano et al, 2014), rupintrivir (AG7088) (targets EV71 protease 3C pro (Dragovich et al, 1999), the peptide LVLQTM (targets 2A pro (Falah et al, 2012), DTriP-22 and aurintricarboxylic acid (target polymerase 3D pol (Chen et al, 2009;Urbinati et al, 2008) and several natural products such as lycorine and raoulic acid (Choi et al, 2009;Liu et al, 2011).…”

Activation de la réponse innée antivirale par des inhibiteurs de la biosynthèse des pyrimidines

“…Cependant, plusieurs groupes qui cherchaient à identifier directement des composés antiviraux dans des tests mesurant la réplication d'un virus en culture ont également isolé des inhibiteurs de cette voie métabolique, et qui ciblent notamment la DHODH [19][20][21][22]25]. Les essais réalisés in vivo chez la souris par ces différentes équipes ont donné des résultats mitigés.…”