Obatoclax, saliphenylhalamide, and gemcitabine inhibit influenza a virus infection.
Influenza A viruses (IAVs) infect humans and cause significant morbidity and mortality. Different treatment options have been developed; however, these were insufficient during recent IAV outbreaks. Here, we conducted a targeted chemical screen in human nonmalignant cells to validate known and search for novel host-directed antivirals. The screen validated saliphenylhalamide (SaliPhe) and identified two novel anti-IAV agents, obatoclax and gemcitabine. Further experiments demonstrated that Mcl-1 (target of obatoclax) provides a novel host target for IAV treatment. Moreover, we showed that obatoclax and SaliPhe inhibited IAV uptake and gemcitabine suppressed viral RNA transcription and replication. These compounds possess broad spectrum antiviral activity, although their antiviral efficacies were virus-, cell type-, and species-specific. Altogether, our results suggest that phase II obatoclax, investigational SaliPhe, and FDA/EMEA-approved gemcitabine represent potent antiviral agents.
Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00290, Finland.
Oxana V
OV
Denisova
Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00290, Finland.
Laura
L
Kakkola
Minerva Foundation Institute for Medical Research, Helsinki FI-00290, Finland.
Lin
L
Feng
Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00290, Finland; Minerva Foundation Institute for Medical Research, Helsinki FI-00290, Finland.
Jakob
J
Stenman
Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00290, Finland.
Ashwini
A
Nagaraj
Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00290, Finland.
Johanna
J
Lampe
Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00290, Finland.
Bhagwan
B
Yadav
Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00290, Finland.
Tero
T
Aittokallio
Institute of Biotechnology, Helsinki FI-00290, Finland.
Pasi
P
Kaukinen
Institute of Biotechnology, Helsinki FI-00290, Finland.
Tero
T
Ahola
Haartman Institute, Helsinki FI-00290, Finland.
Suvi
S
Kuivanen
Haartman Institute, Helsinki FI-00290, Finland; Helsinki University Hospital Laboratory, Helsinki FI-00290, Finland.
Olli
O
Vapalahti
Helsinki University Hospital Laboratory, Helsinki FI-00290, Finland.
Anu
A
Kantele
National Institute for Health and Welfare, Helsinki FI-00290, Finland.
Janne
J
Tynell
National Institute for Health and Welfare, Helsinki FI-00290, Finland.
Ilkka
I
Julkunen
Institute of Clinical Medicine, Helsinki FI-00290, Finland.
Hannimari
H
Kallio-Kokko
Department of Virology, University of Turku, Turku FI-20520, Finland.
Henrik
H
Paavilainen
Department of Virology, University of Turku, Turku FI-20520, Finland.
Veijo
V
Hukkanen
Centre for Biomolecular Sciences, University of St. Andrews, Fife KY16 9ST, United Kingdom.
Richard M
RM
Elliott
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038.
Jef K
JK
De Brabander
Department for Molecular Biomedical Research, VIB and Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium.
Xavier
X
Saelens
Institute for Molecular Medicine Finland, FIMM, Helsinki FI-00290, Finland. Electronic address: denis.kainov@helsinki.fi.
Denis E
DE
Kainov
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D007211:Indoles; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000502:physiology*; D007251:Influenza, Human / Q000188:drug therapy* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis; D012459:Salicylates / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication; D000093542:Gemcitabine
D000577:Amides; D000998:Antiviral Agents; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D012367:RNA, Viral; D012459:Salicylates; C574373:saliphenylhalamide; D003841:Deoxycytidine; C520962:obatoclax; D000093542:Gemcitabine