Obatoclax, Saliphenylhalamide, and Gemcitabine Inhibit Influenza A Virus Infection

被引：72

作者：

Denisova, Oxana V. ^{[1
]}

Kakkola, Laura ^{[1
]}

Feng, Lin ^{[2
]}

Stenman, Jakob ^{[1
,2
]}

Nagaraj, Ashwini ^{[1
]}

Lampe, Johanna ^{[1
]}

Yadav, Bhagwan ^{[1
]}

Aittokallio, Tero ^{[1
]}

Kaukinen, Pasi ^{[3
]}

Ahola, Tero ^{[3
]}

Kuivanen, Suvi ^{[4
]}

Vapalahti, Olli ^{[4
,5
]}

Kantele, Anu ^{[5
]}

Tynell, Janne ^{[6
]}

Julkunen, Ilkka ^{[6
]}

Kallio-Kokko, Hannimari ^{[7
]}

Paavilainen, Henrik ^{[8
]}

Hukkanen, Veijo ^{[8
]}

Elliott, Richard M. ^{[9
]}

De Brabander, Jef K. ^{[10
]}

Saelens, Xavier ^{[11
,12
]}

Kainov, Denis E. ^{[1
]}

机构：

[1] FIMM, Inst Mol Med Finland, FI-00290 Helsinki, Finland

[2] Minerva Fdn, Inst Med Res, FI-00290 Helsinki, Finland

[3] Inst Biotechnol, FI-00290 Helsinki, Finland

[4] Haartman Inst, FI-00290 Helsinki, Finland

[5] Helsinki Univ Hosp Lab, FI-00290 Helsinki, Finland

[6] Natl Inst Hlth & Welf, FI-00290 Helsinki, Finland

[7] Inst Clin Med, FI-00290 Helsinki, Finland

[8] Univ Turku, Dept Virol, FI-20520 Turku, Finland

[9] Univ St Andrews, Ctr Biomol Sci, St Andrews KY16 9ST, Fife, Scotland

[10] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA

[11] VIB, Dept Mol Biomed Res, B-9000 Ghent, Belgium

[12] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2012年 / 287卷 / 42期

基金：

美国国家卫生研究院; 芬兰科学院;

关键词：

APOPTOSIS; CELLS; NUCLEOSIDE; EXPRESSION; PROTEINS; AGENTS; MCL-1;

D O I：

10.1074/jbc.M112.392142

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：35324 / 35332

页数：9

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