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Drug mimics human antibody against flu

Researchers are working to develop ways to neutralize multiple strains of influenza virus, shown here. bodym / iStock / Thinkstock

CDC estimates that in 2017-2018 the influenza (flu) vaccine prevented 7 million illnesses and 8,000 deaths. But not everyone gets the annual vaccine, and flu viruses sicken millions every year. To prevent more illnesses, a universal flu vaccine is under development. It would work against all flu viruses so that people wouldn’t need a shot each year.

Scientists are also trying to develop new treatments based on the neutralizing antibodies found in people who’ve had flu. These antibodies bind to a flu protein called hemagglutinin (HA) and prevent the virus from entering a cell. Previous studies have shown that although the head region of HA varies by flu strain, the HA stem is more stable. An antibody or drug that binds to the HA stem could neutralize many strains of flu virus.

A team led by Dr. Ian A. Wilson at the Scripps Research Institute and Dr. Maria J.P. van Dongen at Janssen Research & Development set out to find a small-molecule drug that could mimic how antibodies bind to the HA stem of the flu virus. The research was supported in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of General Medical Sciences (NIGMS). The findings were reported in Science on March 8, 2019.

Influenza A viruses, which can cause pandemics, can be separated into two groups based on their HA subtype. Broadly neutralizing antibodies usually bind to group 1 or to group 2 viruses, but a few can target both. The researchers screened a library of about 500,000 small-molecule compounds for the ability to mimic an antibody called CR6261, which neutralizes most group 1 influenza A viruses by blocking the HA stem from attaching to human cells.

The team found 9,000 compounds that were able to bind to the HA stem. Of the 300 that did well on repeated tests, the team selected JNJ7918 as the best candidate for neutralizing flu strains.

Next, the researchers modified the structure of JNJ7918 to enhance its binding ability. The research team made several modifications to the structure to improve its activity. The resulting compound, called JNJ4796, protected all mice from death when given by mouth after exposure to flu virus.

Next, the research team tested JNJ4796 in a system designed to mimic the human airway using cells from donors. After the airway cells were infected by flu virus, JNJ4796 was able to eliminate much of the virus during the first 96 hours.

Both lab tests and crystal structure analysis revealed that JNJ4796 and CR6261 have similar ways of binding to the HA stem. But CR6261 is a large antibody that needs to be injected rather than swallowed to avoid destruction in the stomach. A small-molecule drug like JNJ4796 could be swallowed instead.

“What’s exciting is that this molecule has the potential to target different strains and subtypes of influenza virus,” Wilson says.

The team’s approach of finding small-molecule drugs that mimic specific human antibodies can also be applied to finding drugs against other viruses.

—by Geri Piazza