What is causing resistance to the new flu drug, Xofluza?

Until recently, there was only one FDA-approved class of anti-viral drugs used to treat influenza in the United States. On October 24, the FDA approved use of a new flu treatment, the first one in nearly 20 years.

Tamiflu and Relenza, brand names that should be familiar to anyone who has suffered with the flu over the years, can help patients get past symptoms a bit faster. But there’s also a small twist — the flu virus has shown the ability to develop resistance to those drugs.

Xofluza, a new flu drug, is approved

Recent development of a breakthrough flu medication called Xofluza, an endonuclease inhibitor, showed promise by approaching the virus in a new way.

Xofluza, approved by the U.S. FDA for patients 12 and older, could lead to reductions in flu cases around the world. However, the development of drug resistance is a major drawback to any antiviral therapy, and endonuclease inhibitors are not excluded from this rule. The virus is set back when treated, but may mutate to block the effects of the drug.

St. Jude scientists recently discovered a mutation that occurs when the virus is exposed to an endonuclease inhibitor. This mutation prevents the new drug from working, but it also laid the groundwork for additional research to potentially bring the virus under control.

The study, led by Elena Govorkova MD, PhD, of Department of Infectious Diseases, appeared in the journal mBio, published by the American Society of Microbiology.

What is an endonuclease inhibitor?

Viruses like influenza are spread through water droplets produced when an infected person coughs or sneezes, and then the virus travels to the nose, mouth or eyes of another person.

Sometimes, the virus will live on a surface long enough to be picked up by an unsuspecting passerby.

In order for the virus to continue to spread, it has to continually copy its own genetic material within the host. An endonuclease is an enzyme within the influenza virus that allows it to copy itself.

When that enzyme is prevented from doing its job, the viral particles cannot reproduce.

As the name suggests, endonuclease inhibitor block the function of the endonuclease by plugging into the slot where it would normally attach and allow for copying of the genetic material. The drug is engineered to fit into the slot much like a key fits into a lock.

Govorkova and her team worked with an investigational inhibitor known as RO-7 — which is similar but not identical to Xofluza.

Identification of the mutation and why it’s important

The key no longer fits the lock

Influenza viruses mutate. It's nothing new to the scientists who study them.

If an effective treatment is found, viruses will change on a structural level to prevent the damage from being done.

When Govorkova’s lab experimented with RO-7, they found that the virus would mutate and change its structure — the "key" would no longer fit the "lock."

This is a setback for the medication, but the discovery and identification of the specific structural changes that happened after exposure to RO-7, and when they happen, it a huge step forward.

By detailing how and when the virus mutates after exposure, the designers of the next generation of drugs can approach their work with a new clarity about what is needed to knock down the infection in less time.

The study paves the way for possible combination therapy to provide a one-two punch that helps destroy the virus' ability to reproduce faster, which limits its ability to mutate and become resistant to antiviral drugs.

This type of treatment has been useful against other viral diseases, such as hepatitis C and HIV.

About the author

Lee Morgan is a Progress contributor at St. Jude Children’s Research Hospital.
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