Novel Dihydroorotate Dehydrogenase Inhibitors with Potent Interferon-Independent Antiviral Activity against Mammarenaviruses In Vitro.

Yu-Jin Kim,Beatrice Cubitt,Hella Kohlhof,Jens H Kuhn,Daniel Vitt,Juan C De La Torre,Yingyun Cai

doi:10.3390/v12080821

Abstract

Mammarenaviruses cause chronic infections in rodents, which are their predominant natural hosts. Human infection with some of these viruses causes high-consequence disease, posing significant issues in public health. Currently, no FDA-licensed mammarenavirus vaccines are available, and anti-mammarenavirus drugs are limited to an off-label use of ribavirin, which is only partially efficacious and associated with severe side effects. Dihydroorotate dehydrogenase (DHODH) inhibitors, which block de novo pyrimidine biosynthesis, have antiviral activity against viruses from different families, including Arenaviridae, the taxonomic home of mammarenaviruses. Here, we evaluate five novel DHODH inhibitors for their antiviral activity against mammarenaviruses. All tested DHODH inhibitors were potently active against lymphocytic choriomeningitis virus (LCMV) (half-maximal effective concentrations [EC50] in the low nanomolar range, selectivity index [SI] > 1000). The tested DHODH inhibitors did not affect virion cell entry or budding, but rather interfered with viral RNA synthesis. This interference resulted in a potent interferon-independent inhibition of mammarenavirus multiplication in vitro, including the highly virulent Lassa and Junín viruses.

Highlights

Mammarenaviruses (Bunyavirales: Arenaviridae: Mammarenavirus) cause chronic asymptomatic infections in their natural reservoir hosts, which are predominantly muroid rodents
A549 cells were infected with recombinant LCMV (rLCMV)/Zoanthus sp. green fluorescent protein (ZsG)-P2A-NP in the presence (5 μM) of the indicated compounds or vehicle control (DMSO)
We investigated the dose-dependent effects of five novel Dihydroorotate dehydrogenase (DHODH) inhibitors (i.e., Cmp 1, Cmp 2, Cmp 3, Cmp 4, and Cmp 5) on rLCMV/ZsG multiplication, cell viability, and in vitro hDHODH inhibition (Figure 1 and Figure 8)

Summary

Introduction

Mammarenaviruses (Bunyavirales: Arenaviridae: Mammarenavirus) cause chronic asymptomatic infections in their natural reservoir hosts, which are predominantly muroid rodents. Some of these viruses are public health threats because they can be transmitted to humans through aerosol transmission or by direct contact of abraded skin with contaminated material [1]. Lassa virus (LASV) in Western Africa and Junín virus (JUNV) in the Argentinian Pampas, can cause severe disease in humans (Lassa fever and Argentinian hemorrhagic fever, respectively), and pose important public health problems in their endemic regions. Evidence indicates that LASV-endemic regions are expanding [5], and the identification of novel zoonotic mammarenaviruses, such as Lujo virus (LUJV), responsible for a cluster of severe infections in humans in Southern Africa in 2009 [6], has raised

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