To develop a potential antiviral treatment, Stanford researchers adopted an unusual approach: Rather than trying to disable viral enzymes, they targeted proteins the infected individual makes — and the virus needs.

A combination of two cancer drugs inhibited both dengue and Ebola virus infections in mice in a study led by Stanford University School of Medicine researchers, despite the fact that these two viruses are vastly different from each other.

In laboratory–dish experiments, the drug combination, which has previously shown efficacy against the hepatitis C virus, also was effective against West Nile and Zika viruses, both of which are relatives of the hepatitis C virus, and multiple other unrelated viruses.

The multi–institution study, published online Feb. 27 in the Journal of Clinical Investigation, also pinpointed the specific molecular mechanism by which these drugs derail a variety of RNA viruses, whose genetic material consists not of DNA but of its close relative, RNA.

“We’ve shown that a single combination of drugs can be effective across a broad range of viruses – even when those viruses hail from widely separated branches of the evolutionary tree,” said the study’s senior author, Shirit Einav, MD, assistant professor of infectious diseases and of microbiology and immunology.

The study’s lead authors are former Stanford postdoctoral scholars Elena Bekerman, PhD, now at Gilead Sciences Inc., and Gregory Neveu, PhD, now at the University of Lyon and French National Institute of Health and Medical Research.

The reason the drugs used in the study are able to combat infections by such different viruses is that their disabling action is directed not at the virus but at proteins of the host cell it’s trying to infect, Einav said.

Einav and her team are investigating strategies for combatting RNA viruses, such as dengue and Ebola. These viruses have a faulty replication process that results in frequent errors as their genetic material is copied, rendering them especially prone to mutations. Consequently, they swiftly acquire resistance to a typical antiviral drug that targets a specific viral enzyme, Einav said.

“The ‘one drug, one bug’ approach can be quite successful, as in the case of hepatitis C virus,” for which a concerted effort has generated several approved antiviral treatments, she said. But it took more than 10 years of research, she noted, and drug development costs typically exceed $2 billion. Making matters worse, Einav added, is the impossibility of predicting what the next emerging viral threat will look like.

The standard antiviral approach aims to disable a specific viral enzyme. Einav and her associates’ alternative approach took advantage of viruses’ total dependence on infected cells’ molecular machinery.

The two–drug drug combination Einav’s team put to work against dengue and Ebola impedes AAK1’s and GAK’s activity, effectively pricing bus fares beyond the viral budget. Erlotinib and sunitinib, each approved by the Food and Drug Administration more than a decade ago, are prescribed for various cancer indications. Neither AAK1 nor GAK are the primary targets of these drugs in their cancer–fighting roles. But Einav’s group discovered, by accessing publicly available databases, that the two drugs impair AAK1 and GAK activity, too.

Einav and her colleagues previously demonstrated that erlotinib and sunitinib inhibit hepatitis C virus infection in cells. In the new study, the investigators conducted experiments in lab dishes to show that both drugs inhibit viral infection by impeding the activity of AAK1 and GAK.

The same drug combination also showed efficacy against a variety of other RNA viruses related to hepatitis C, including the Zika and West Nile viruses, and even against several unrelated viruses.