New Cell Screening Technique Highlights Antiviral Potential of Known Anticancer Drugs

Three candidate anticancer drugs have been found to be potent blockers of invasion of mammalian cells by the Influenza A virus (IAV).

Currently available antiviral drugs target viral proteins, and due to the high mutation rate among the influenza viruses, the virus quickly develops resistance to them. For that reason, next-generation antiviral drugs should be directed towards host cell functions.

Investigators at the University of Helsinki (Finland) conducted a targeted chemical screen in human nonmalignant cells to validate known and search for novel host-directed antivirals. They reported in the August 21, 2012, online edition of the Journal of Biological Chemistry that the screen validated saliphenylhalamide (SaliPhe) and identified two novel anti-IAV agents, obatoclax and gemcitabine.

The natural product salicylihalamide is a potent inhibitor of the vacuolar ATPase (V-ATPase), a potential target for antitumor chemotherapy. This finding led to the development of a method for the multigram synthesis of the potent salicylihalamide analog saliphenylhalamide.

Obatoclax is an inhibitor of the Bcl-2 family of proteins. This inhibition induces apoptosis in cancer cells, preventing tumor growth.

Gemcitabine is a nucleoside analog in which the hydrogen atoms on the 2' carbon of deoxycytidine are replaced by fluorine atoms. As with fluorouracil and other analogues of pyrimidines, the triphosphate analogue of gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumor growth, as only one additional nucleoside can be attached to the "faulty" nucleoside, resulting in apoptosis. Gemcitabine was first synthesized during the early 1980s as an antiviral drug, but preclinical testing showed that it killed leukemia cells in vitro.

Further experiments demonstrated that Mcl-1 (target of obatoclax) provided a novel host target for IAV treatment. Obatoclax and SaliPhe inhibited IAV uptake and gemcitabine suppressed viral RNA transcription and replication. These compounds possessed broad-spectrum antiviral activity, although their antiviral efficacies were virus, cell type-, and species-specific.

Altogether, these results suggest that phase II obatoclax, investigational SaliPhe, and FDA ([US] Food and Drug Administration)/EMEA (European Medicines Evaluation Agency) - approved gemcitabine represent potent antiviral agents.

"An interesting aspect of this study is that the antiviral effects of obatoclax, saliphenylhalamide, and gemcitabine, which all are either investigational or approved anticancer agents, are achieved at much lower concentrations than that needed to mediate cancer cell death," said senior author Dr. Denis Kainov, professor of molecular medicine at the University of Helsinki.

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