Unique Small Molecule Entry Inhibitors of Hemorrhagic Fever Arenaviruses

Andrew M Lee,Jillian M Rojek,Christina F Spiropoulou,Anette T Gundersen,Wei Jin,Alex Shaginian,Joanne York,Jack H Nunberg,Dale L Boger,Michael B.A Oldstone,Stefan Kunz

doi:10.1074/jbc.m802089200

Abstract

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.

Highlights

Several arenaviruses, including the Old World virus Lassa virus (LASV)3 and the New World arenaviruses Junin (JUNV), Guanarito (GTOV), and Machupo (MACV), cause severe viral hemorrhagic fevers in humans and represent a serious public health problem [1]
A notable difference between LASV and the pathogenic New World arenaviruses is their use of distinct primary cellular receptors, with LASV employing ␣-dystroglycan (␣-DG) [8] and JUNV, MACV, GTOV, and Sabia virus using transferrin receptor 1 (TfR1) [9]
Our screening efforts resulted in the discovery of a series of novel small inhibitors of viral entry that are highly effective against both Old World and New World hemorrhagic arenaviruses

Summary

Introduction

Several arenaviruses, including the Old World virus Lassa virus (LASV)3 and the New World arenaviruses Junin (JUNV), Guanarito (GTOV), and Machupo (MACV), cause severe viral hemorrhagic fevers in humans and represent a serious public health problem [1]. Broad Activity of Candidate Compounds against Human Pathogenic Arenaviruses—The South American hemorrhagic fever (HF) viruses JUNV, GTOV, and MACV are genetically and structurally distinct from the Old World arenavirus LASV and show different receptor usage.

Results

Conclusion