New drug neutralizes influenza virus by overloading it with mutation

Considered to be one of the most important public health problems worldwide, influenza is a seasonal infectious disease with high morbidity (between 300,000 and 500,000 deaths worldwide each year). In addition to vaccines for prevention, therapeutic molecules exist to treat flu-like symptoms, such as oseltamivir (Tamiflu). However, these drugs are generally very effective and face the development of viral resistance. But recently, a team of virologists has developed a new drug neutralizing the virus by "choking" mutations, without developing resistant strains.

Doctors often warn against the risk of rapid spread of pandemic pathogens worldwide. But a virus is already crossing the world every year, causing tens of millions of infections and hundreds of thousands of deaths: the flu. A new drug, which has been very effective on ferrets, could significantly reduce this balance. The study was published in the journal Science Translational Medicine.

This molecule appears to be more effective than the commonly used treatment oseltamivir, and preliminary results show that it is less favorable than the latter for the development of resistance in the short and medium term. Virologists must accommodate the rapid mutation rate of the influenza virus, which requires an annual reformulation of influenza vaccines to target commonly circulating strains.

The low efficacy of traditional anti-flu drugs

The flu is a real danger for some weakened people and vaccination coverage is not always optimal. Meanwhile, new flu drugs have been slow to develop and those that exist are often inadequate. Oste- tamivir, for example, provides at best moderate benefit, and only when it is given early in the infection.

The influenza virus has two surface proteins: hemagglutinin (H) and neuraminidase (N). The latter allows him to attach to the cell wall to infect them (A). Anti-viral drugs such as oseltamivir are neuraminidase inhibitors, that is, they inactivate the viral protein (B); the virus can no longer attach itself to cells or multiply. Credits: Anne Moscona

In addition, the influenza virus has developed resistance to oseltamivir and an older drug, amantadine. In addition, influenza strains resistant to baloxavir have already been reported, a drug approved by the US Food and Drug Administration (FDA) just last year.

EID-2801: very encouraging results in the ferret

To find an alternative, scientists at Georgia State University and Emory University , both in Atlanta, studied a compound called N-hydroxycytidine (NHC), known for years to inhibit a wide range of RNA viruses, like the flu. Previously, researchers had shown that NHC was active against the flu. But in tests on monkeys, they discovered that the body was not absorbing the medicine.

The researchers modified the structure of the NHC to create a new compound called EIDD-2801, which is converted back into NHC inside the body. They then tested it on ferrets, the most used animal model for the flu.

If the ferrets received the compound 12 hours after infection, they did not develop any disease. Those who received it 24 hours after the onset of fever still produced fewer viruses than control animals treated with oseltamivir or who received no treatment. The fever was also neutralized more quickly.

Analyzes showing a reduction in viral load in the ferret, 3.5 days after infection; the comparison is made between EIDD-2801 and oseltamivir. Credits: Mart Toots et al. 2019

Reducing the symptoms in ferrets is important because it allows us to predict what would happen to humans, " says Andrew Pavia, an infectious disease specialist at the University of Utah. " This is a major step in the development of a drug for humans.

Overload the mutations virus to cause a "disaster error"

Researchers investigated how NHC blocks influenza by sequencing the genomes of influenza viruses exposed to the compound. They discovered that the virus incorporated the drug into its RNA when it replicated, instead of a molecule called cytosine, which resulted in a series of errors that virologists call "catastrophe error", essentially screening the virus for mutations.

The researchers also developed the virus while keeping it exposed to sublethal doses of NHC, or by slowly increasing the concentration of NHC, methods that do not kill the virus, but give it a chance to test its resistance to EIDD- 2801. Although sequencing clearly shows that the virus is trying to resist the drug, no resistant strain has developed.

Clinical trials planned soon

But that does not mean that resistance can not develop, says Albert Osterhaus, a virologist at the University of Veterinary Medicine in Hanover, Germany. Favipiravir, a drug approved in 2014 in Japan to fight against pandemic influenza viruses and resistant to all other drugs, was supposed to offer a similar barrier to resistance before the development of resistant strains.

According to Plemper, additional animal toxicity testing did not trigger alarm signals and the first trials of EIDD-2801 in humans are expected to begin next spring. Pavia says the new drug could possibly be used in combination with other drugs to fight against resistance, a strategy already used for the treatment of HIV and hepatitis B.



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