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

2019; American Association for the Advancement of Science; Volume: 363; Issue: 6431 Linguagem: Inglês

10.1126/science.aar6221

1095-9203

Maria J. P. van Dongen, Rameshwar U. Kadam, Jarek Juraszek, Edward C. Lawson, Boerries Brandenburg, Frederike Schmitz, Wim Schepens, Bart Stoops, Harry A. van Diepen, Mandy Jongeneelen, Chan Tang, Jan Vermond, Alida van Eijgen-Obregoso Real, Sven Blokland, Divita Garg, Wenli Yu, Wouter Goutier, Ellen A. Lanckacker, J. Klap, Danielle Peeters, Jin Wu, Christophe Buyck, Tim H. M. Jonckers, Dirk Roymans, Peter Roevens, Ronald Vogels, Wouter Koudstaal, Robert H. Friesen, Pierre Raboisson, Dashyant Dhanak, Jaap Goudsmit, Ian A. Wilson,

Respiratory viral infections research

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.