| Literature DB >> 30846569 |
Maria J P van Dongen1,2, Rameshwar U Kadam3, Jarek Juraszek4, Edward Lawson5, Boerries Brandenburg4,6, Frederike Schmitz4, Wim B G Schepens2, Bart Stoops2, Harry A van Diepen4, Mandy Jongeneelen4,6, Chan Tang4,6, Jan Vermond4, Alida van Eijgen-Obregoso Real4, Sven Blokland4,6, Divita Garg7, Wenli Yu3, Wouter Goutier4, Ellen Lanckacker8, Jaco M Klap4, Daniëlle C G Peeters2, Jin Wu8, Christophe Buyck2, Tim H M Jonckers8, Dirk Roymans8, Peter Roevens2, Ronald Vogels4,6, Wouter Koudstaal4, Robert H E Friesen4, Pierre Raboisson8, Dashyant Dhanak2,5, Jaap Goudsmit4,9, Ian A Wilson10,11.
Abstract
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.Entities:
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Year: 2019 PMID： 30846569 PMCID： PMC6457909 DOI： 10.1126/science.aar6221
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728