Unique small molecule entry inhibitors of hemorrhagic fever arenaviruses.
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.
Lee
Andrew M
AM
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA.
Rojek
Jillian M
JM
Spiropoulou
Christina F
CF
Gundersen
Anette T
AT
Jin
Wei
W
Shaginian
Alex
A
York
Joanne
J
Nunberg
Jack H
JH
Boger
Dale L
DL
Oldstone
Michael B A
MB
Kunz
Stefan
S
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D001117:Arenaviridae Infections / Q000188:drug therapy*; D018050:Arenavirus; D002522:Chlorocebus aethiops; D021821:Communicable Diseases, Emerging / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006482:Hemorrhagic Fevers, Viral / Q000188:drug therapy*; D006801:Humans; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors*; D014771:Virion / Q000378:metabolism
D000998:Antiviral Agents; D014760:Viral Fusion Proteins