Promising peptide fusion inhibitors developed against influenza

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Researchers from the Scripps Research Institute (CA, USA) and Janssen Research & Development (NJ, USA) have designed artificial peptide molecules capable of neutralizing a broad range of influenza viruses and the potential to be developed for influenza therapeutics in the future.

Novel antivirals are urgently required against influenza virus to combat potential pandemics and emerging or mutating viruses. This study, published recently in Science, reports a set of four potent peptide fusion inhibitors against influenza hemagglutinin, and demonstrates that these peptides can block infectivity against many circulating flu strains, including H1N1 and H5N1.

The peptides are designed to mimic the binding regions of two recently discovered influenza ‘super antibodies’ termed FI6v3 and CR9114, which have been demonstrated to neutralize almost all influenza A strains. The peptides, however, have advantages over the antibodies they are based on, for example, these inhibitors have the potential to be delivered via tablets, as opposed to injection or infusion.

Co-senior investigator, Ian Wilson (Scripps Research Institute), commented: “Making small molecules that do essentially what these larger, broadly neutralizing antibodies do is a really exciting and promising strategy against influenza, as our new results show.”

Wilson and the team mapped the antibodies at an atomic scale, using this data to design novel proteins that bind to the flu virus in similar manner. The team then undertook several rounds of molecular design and synthesis, in addition to virus-binding tests and structural evaluation, to optimize the set of four cyclic peptides. The team went on to demonstrate that these peptides have a high binding affinity for influenza A viruses and an ability to neutralize influenza infections infections.

Author, Rameshwar Kadam (Scripps Research Institute), explained: “These peptides have drug-like stability and will be good candidates for further testing of antiviral efficacy in animal models.

“It’s pretty revolutionary that we were able to use structural information on antibodies to make much smaller molecules that have almost the same binding affinity and breadth of neutralization against flu viruses.”

Wilson concluded: “There has been skepticism in the field that we could get such good results with such small molecules, but this study proves that we can.”

Sources: Kadam RU, Juraszek J, Brandenburg B et al. Potent peptidic fusion inhibitors of influenza virus. Science. doi:10.1126/science.aan0516 (2017) (Epub ahead of print); www.scripps.edu/news/press/2017/20170928KadamWilson.html

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