TY - JOUR
T1 - Obatoclax, Saliphenylhalamide, and Gemcitabine Inhibit Influenza A Virus Infection
AU - Denisova, Oxana V.
AU - Kakkola, Laura
AU - Feng, Lin
AU - Stenman, Jakob
AU - Nagaraj, Ashwini
AU - Lampe, Johanna
AU - Yadav, Bhagwan
AU - Aittokallio, Tero
AU - Kaukinen, Pasi
AU - Ahola, Tero
AU - Kuivanen, Suvi
AU - Vapalahti, Olli
AU - Kantele, Anu
AU - Tynell, Janne
AU - Julkunen, Ilkka
AU - Kallio-Kokko, Hannimari
AU - Paavilainen, Henrik
AU - Hukkanen, Veijo
AU - Elliott, Richard M.
AU - De Brabander, Jef K.
AU - Saelens, Xavier
AU - Kainov, Denis E.
PY - 2012/10/12
Y1 - 2012/10/12
N2 - 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.
AB - 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.
U2 - 10.1074/jbc.M112.392142
DO - 10.1074/jbc.M112.392142
M3 - Article
SN - 0021-9258
VL - 287
SP - 35324
EP - 35332
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 42
ER -