Host Cell Factors as Antiviral Targets in Arenavirus Infection

Abstract

Among the members of the Arenaviridae family, Lassa virus and Junin virus generate periodic annual outbreaks of severe human hemorrhagic fever (HF) in endemic areas of West Africa and Argentina, respectively. Given the human health threat that arenaviruses represent and the lack of a specific and safe chemotherapy, the search for effective antiviral compounds is a continuous demanding effort. Since diverse host cell pathways and enzymes are used by RNA viruses to fulfill their replicative cycle, the targeting of a host process has turned an attractive antiviral approach in the last years for many unrelated virus types. This strategy has the additional benefit to reduce the serious challenge for therapy of RNA viruses to escape from drug effects through selection of resistant variants triggered by their high mutation rate. This article focuses on novel strategies to identify inhibitors for arenavirus therapy, analyzing the potential for antiviral developments of diverse host factors essential for virus infection.

Inhibition of Arenavirus by A3, a Pyrimidine Biosynthesis Inhibitor

“…Previous studies have documented that inhibitors of cytosine triphosphate synthetase (29) and OMPD (31) exhibit antiarenaviral activity, but their potency is lower than that of ribavirin (25). We observed that the magnitude of the antiarenaviral activity of A3 was significantly higher in human A549 cells than in hamster BHK-21 cells, a finding consistent with reported cell-species-dependent differences on the antiviral activity of A3 against influenza virus (32).…”

“…Notably, the antiviral and mutagenic activities of ribavirin could not be accounted for solely by depletion of intracellular GTP levels, which are a consequence of IMPDH inhibition (24)(25)(26)(27)(28). Several other compounds, including cytidine analogs that target cytosine triphosphate synthetase (29), analogs of adenosine that target S-adenosylhomocysteine hydrolase and interfere with the 5= cap of mRNA (30), and carbanucleoside analogs that target orotidylic acid decarboxylase (OMPD) and inhibit the conversion of OMP to UMP (31), have been shown to have antiarenaviral activities but did not exhibit advantages over ribavirin (25). Recently, a screen for inhibitors of influenza virus replication in cultured cells identified the de novo pyrimidine biosynthesis inhibitor compound A3 (32), which was found to have a broad inhibitory effect on multiplication of several other RNA viruses, including Newcastle disease virus, vesicular stomatitis virus, Sindbis virus, hepatitis C virus, West Nile virus, and dengue virus (32).…”

Annexins in Translational Research: HIDDEN Treasures to Be Found

“…To overcome the emergence of drug-resistant viruses, bacteria, and fungi, therapeutic strategies that aim at targeting host cell factors rather than the pathogen itself are currently pursued [110]. However, most of these novel approaches are still in very early phases of clinical trials.…”

Emerging functions as host cell factors – an encyclopedia of annexin-pathogen interactions

“…Prominent examples for this are penicillin and amantadine (WHO, 2014). This is expected to be more unlikely for drugs that target host factors (Linero et al, 2012). Given that infectious diseases still account for many deaths worldwide, mainly in poorer societies, suitable therapeutic approaches are needed.…”

“…Pathogens rely on their host and the host environmental conditions and are therefore highly adapted to both. Because of their often high mutation rate and the transfer of mobile genetic elements (Stokes and Gillings, 2011;Linero et al, 2012), viruses and bacteria acquire resistance to drugs that target pathogen components. Prominent examples for this are penicillin and amantadine (WHO, 2014).…”