A broad-spectrum antiviral targeting entry of enveloped viruses.
We describe an antiviral small molecule, LJ001, effective against numerous enveloped viruses including Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically intercalated into viral membranes, irreversibly inactivated virions while leaving functionally intact envelope proteins, and inhibited viral entry at a step after virus binding but before virus-cell fusion. LJ001 pretreatment also prevented virus-induced mortality from Ebola and Rift Valley fever viruses. Structure-activity relationship analyses of LJ001, a rhodanine derivative, implicated both the polar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus-cell but not cell-cell fusion, and further studies with lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic window that exists between static viral membranes and biogenic cellular membranes with reparative capacity. In sum, our data reveal a class of broad-spectrum antivirals effective against enveloped viruses that target the viral lipid membrane and compromises its ability to mediate virus-cell fusion.
Wolf
Mike C
MC
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90025, USA.
Freiberg
Alexander N
AN
Zhang
Tinghu
T
Akyol-Ataman
Zeynep
Z
Grock
Andrew
A
Hong
Patrick W
PW
Li
Jianrong
J
Watson
Natalya F
NF
Fang
Angela Q
AQ
Aguilar
Hector C
HC
Porotto
Matteo
M
Honko
Anna N
AN
Damoiseaux
Robert
R
Miller
John P
JP
Woodson
Sara E
SE
Chantasirivisal
Steven
S
Fontanes
Vanessa
V
Negrete
Oscar A
OA
Krogstad
Paul
P
Dasgupta
Asim
A
Moscona
Anne
A
Hensley
Lisa E
LE
Whelan
Sean P
SP
Faull
Kym F
KF
Holbrook
Michael R
MR
Jung
Michael E
ME
Lee
Benhur
B
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000378:metabolism; D014777:Virus Diseases / Q000188:drug therapy*; D053586:Virus Internalization / Q000187:drug effects*
D000998:Antiviral Agents; C549213:LJ001 compound; D014759:Viral Envelope Proteins; D012236:Rhodanine