A small-molecule fusion inhibitor of influenza virus is orally active in mice

Science. 2019 Mar 8;363(6431):eaar6221. doi: 10.1126/science.aar6221.


Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality. Our lead compound neutralizes influenza A group 1 viruses by inhibiting HA-mediated fusion in vitro, protects mice against lethal and sublethal influenza challenge after oral administration, and effectively neutralizes virus infection in reconstituted three-dimensional cell culture of fully differentiated human bronchial epithelial cells. Cocrystal structures with H1 and H5 HAs reveal that the lead compound recapitulates the bnAb hotspot interactions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antibodies, Neutralizing / chemistry*
  • Biomimetic Materials / administration & dosage
  • Biomimetic Materials / pharmacokinetics
  • Biomimetic Materials / pharmacology*
  • Bronchi / virology
  • Cells, Cultured
  • Dogs
  • Hemagglutinin Glycoproteins, Influenza Virus / genetics
  • Hemagglutinin Glycoproteins, Influenza Virus / metabolism
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects*
  • Influenza, Human / prevention & control*
  • Madin Darby Canine Kidney Cells
  • Mice
  • Piperazines / administration & dosage
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Respiratory Mucosa / virology
  • Viral Fusion Protein Inhibitors / administration & dosage
  • Viral Fusion Protein Inhibitors / pharmacokinetics
  • Viral Fusion Protein Inhibitors / pharmacology*
  • Virus Internalization / drug effects*


  • Antibodies, Neutralizing
  • H1N1 virus hemagglutinin
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Piperazines
  • Viral Fusion Protein Inhibitors
  • hemagglutinin, avian influenza A virus