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Dan Kalman, pathology, Abl, tyrosine kinases, tuberculosis, smallpox, antiviral, host
Class of anticancer drugs can block Ebola virus replication

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Holly Korschun

Ebola virus

Image credit: CDC

A class of anti-cancer drugs may be effective against the deadly Ebola virus. Nilotinib, a drug approved in the United States and Europe for the treatment of leukemia and known under the trade name Tasigna, can inhibit the ability of Ebola virus to replicate in the laboratory, scientists have discovered.

The results were published Wednesday in the journal Science Translational Medicine.

Daniel Kalman, PhD and his colleagues have previously shown that nilotinib and related cancer drugs such as Gleevec could be used to fight a surprising variety of diseases, including both smallpox and tuberculosis. These drugs shut down human enzymes that some bacteria and viruses exploit, and which are dysregulated in certain cancers. These enzymes are known as Abl-family tyrosine kinases.

“We had suspected for a long time that many viruses might be using the same enzymes, at the point where they emerge from an infected cell,” says Kalman, who is associate professor of pathology and laboratory medicine at Emory University School of Medicine.

To test this idea, Kalman teamed up with Gary Nabel, MD, PhD, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and his colleagues to test whether this hypothesis  could be applied to Ebola virus infection.

Ebola virus is a member of a family of viruses that cause a hemorrhagic fever. Left untreated, mortality rates often exceed 75 percent. Cases and outbreaks have beenreported in central Africa since its discovery in 1976. No viral-specific therapies are available commercially, though candidate vaccines and antivirals for Ebola are under development.

The first author of the paperwas NIH research fellow Mayra Garcia, PhD. All studies involving the Ebola virus were performed in a BSL4 (biosafety level 4) facility at Texas Biomedical Research Institute in San Antonio under the direction of Ricardo Carrion, PhD.

Inhibition of the Abl family of enzymes decreased the release of assembled viral particles from infected cells, the researchers found.  Nilotinib could reduce viral production by infected cells by up to 10,000 fold.

“Often in this disease if you can just shave a little bit of the viral load off of the infection, if you can just lower it tenfold even, that's what's going to give people a chance to survive it,”  Nabel told the San Antonio News Express. “That's really what we're aiming to do.”

One potential advantage for using drugs that affect host enzymes is that the virus is unlikely to be able to mutate around the obstacle and generate a drug-resistant strain, Kalman says. In addition, data on the safety and potential side effects of nilotinib and its relatives are already available. Nilotinib and imatinib derive their cancer-fighting power from their ability to block Abl enzymes, which are on overdrive in chronic myelogenous leukemia.

Garcia, NIH co-author Arik Cooper, Kalman and Nabel are listed on a patent, “C-Abl Tyrosine Kinase Inhibitors Useful For Inhibiting Filovirus Replication” #61/447,298, filed by the NIH. Kalman is listed on additional intellectual property applications filed by Emory University related to tyrosine kinases, and is entitled to royalties from Inhibikase Therapeutics. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies.  

Reference: M. García, A. Cooper, W. Shi, W. Bornmann, R. Carrion, D. Kalman, G. J. Nabel. Productive replication of Ebola virus is regulated by the c-Abl1 tyrosine kinase. Sci. Transl. Med. 4, 123ra24 (2012).

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