A small-molecule fusion inhibitor of influenza virus is orally active in mice.
Maria J P van DongenRameshwar U KadamJarek JuraszekEdward LawsonBoerries BrandenburgFrederike SchmitzWim B G SchepensBart StoopsHarry A van DiepenMandy JongeneelenChan TangJan VermondAlida van Eijgen-Obregoso RealSven BloklandDivita GargWenli YuWouter GoutierEllen LanckackerJaco M KlapDaniëlle C G PeetersJin WuChristophe BuyckTim H M JonckersDirk RoymansPeter RoevensRonald VogelsWouter KoudstaalRobert H E FriesenPierre RaboissonDashyant DhanakJaap GoudsmitIan A WilsonPublished in: Science (New York, N.Y.) (2019)
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.
Keyphrases
- small molecule
- clinical trial
- high fat diet induced
- endothelial cells
- healthcare
- transcription factor
- signaling pathway
- protein protein
- randomized controlled trial
- type diabetes
- induced pluripotent stem cells
- mass spectrometry
- metabolic syndrome
- high density
- dengue virus
- dna methylation
- study protocol
- zika virus
- genetic diversity
- hyaluronic acid
- disease virus