Search

Hemorrhagic fevers caused by arenaviruses are among the most devastating emerging human diseases. Considering the number of individuals affected, the current lack of a licensed vaccine, and the limited therapeutic options, arenaviruses are arguably among the most neglected tropical pathogens and the development of efficacious anti-arenaviral drugs is of high priority. Over the past years significant efforts have been undertaken to identify novel potent inhibitors of arenavirus infection. High throughput screening of small molecule libraries employing pseudotype platforms led to the discovery of several potent and broadly active inhibitors of arenavirus cell entry that are effective against the major hemorrhagic arenaviruses. Mechanistic studies revealed that these novel entry inhibitors block arenavirus membrane fusion and provided novel insights into the unusual mechanism of this process. The success of these approaches highlights the power of small molecule screens in antiviral drug discovery and establishes arenavirus membrane fusion as a robust drug target. These broad screenings have been complemented by strategies targeting cellular factors involved in productive arenavirus infection. Approaches targeting the cellular protease implicated in maturation of the fusion-active viral envelope glycoprotein identified the proteolytic processing of the arenavirus glycoprotein precursor as a novel and promising target for anti-arenaviral strategies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Viral hemorrhagic fevers caused by the arenaviruses Lassa virus in Africa and Machupo, Guanarito, Junin, and Sabia virus in South America are among the most devastating emerging human diseases with fatality rates of 15-35% and a limited antiviral therapeutic repertoire available. Here we used high throughput screening of synthetic combinatorial small molecule libraries to identify inhibitors of arenavirus infection using pseudotyped virion particles bearing the glycoproteins (GPs) of highly pathogenic arenaviruses. Our screening efforts resulted in the discovery of a series of novel small molecule inhibitors of viral entry that are highly active against both Old World and New World hemorrhagic arenaviruses. We observed potent inhibition of infection of human and primate cells with live hemorrhagic arenaviruses (IC(50)=500-800 nm). Investigations of the mechanism of action revealed that the candidate compounds efficiently block pH-dependent fusion by the arenavirus GPs (IC(50) of 200-350 nm). Although our lead compounds were potent against phylogenetically distant arenaviruses, they did not show activity against other enveloped viruses with class I viral fusion proteins, indicating specificity for arenavirus GP-mediated membrane fusion.

Abstract: The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) represents a powerful experimental model for the study of the basic virology and pathogenesis of arenaviruses. In the present study, we used the LCMV model to evaluate the anti-viral potential of phosphorothioate oligonucleotides against arenaviruses. Our findings indicate that amphipathic DNA polymers (APs) are potent inhibitors of infection with a series of LCMV isolates with IC50 in the low nanomolar range. APs target the surface glycoprotein (GP) of LCMV and block viral entry and cell–cell propagation of the virus, without affecting later steps in replication or release of progeny virus from infected cells. The anti-viral action of APs is sequence-independent but is critically dependent on their size and hydrophobicity. Mechanistically, we provide evidence that APs disrupt the interaction between LCMVGP and its cellular receptor, α-dystroglycan. Exposure of LCMV to APs does not affect the stability of the GP virion spike and has no effect on the conformation of a neutralizing antibody epitope, suggesting rather subtle changes in the conformation and/or conformational dynamics of the viral GP. [Copyright &y& Elsevier]