GSK983: a novel compound with broad-spectrum antiviral activity.
GSK983, a novel tetrahydrocarbazole, inhibits the replication of a variety of unrelated viruses in vitro with EC(50) values of 5-20 nM. Both replication of the adenovirus Ad-5 and the polyoma virus SV-40, and episomal maintenance of human papillomaviruses (HPV) and Epstein-Barr virus (EBV) are susceptible to GSK983. The compound does not inhibit all viruses; herpes simplex virus (HSV-1), human immunodeficiency virus (HIV), and lytic replication of EBV were not susceptible at concentrations below 1 microM. GSK983 does inhibit the growth of cell lines immortalized by HTLV-1, EBV, HPV, SV40 and Ad-5, with EC(50) values in the range of 10-40 nM. Depending on the cell line, the compound induces either apoptosis or cytostasis at concentrations over 20 nM. GSK983 also inhibits cell lines immortalized by non-viral mechanisms, but has little effect on primary cells. The CC(50) values for keratinocytes, fibroblasts, lymphocytes, endothelial, and bone marrow progenitor cells are all above 10 microM. The pattern of inhibition, which includes diverse viruses as well as growth of immortalized cells of varied origins, suggests the target is a host cell protein, rather than a viral protein. Preliminary mechanism studies indicate that GSK983 acts by inducing a subset of interferon-stimulated genes.
Harvey
Robert
R
Infectious Diseases Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Brown
Kevin
K
Zhang
Qin
Q
Gartland
Margaret
M
Walton
Leslie
L
Talarico
Christine
C
Lawrence
Wendell
W
Selleseth
Dean
D
Coffield
Neil
N
Leary
Jeffry
J
Moniri
Kelly
K
Singer
Sara
S
Strum
Jay
J
Gudmundsson
Kristjan
K
Biron
Karen
K
Romines
Karen R
KR
Sethna
Phiroze
P
D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D004267:DNA Viruses / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D002227:Carbazoles; C541365:N-((1R)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-2-pyridinecarboxamide