6CF7

Crystal structure of the A/Solomon Islands/3/2006(H1N1) influenza virus hemagglutinin in complex with small molecule JNJ4796

Summary for 6CF7

• Entry DOI: 10.2210/pdb6cf7/pdb
• Descriptor: Hemagglutinin, alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: glycoprotein, ectodomain, n-glycosylation, viral protein
• Biological source: Influenza A virus (A/Solomon Islands/3/2006(H1N1)); More
• Total number of polymer chains: 2
• Total formula weight: 59322.77

Authors

Kadam, R.U.,Wilson, I.A. (deposition date: 2018-02-13, release date: 2019-02-13, Last modification date: 2024-11-06)

Primary citation

van Dongen, M.J.P.,Kadam, R.U.,Juraszek, J.,Lawson, E.,Brandenburg, B.,Schmitz, F.,Schepens, W.B.G.,Stoops, B.,van Diepen, H.A.,Jongeneelen, M.,Tang, C.,Vermond, J.,van Eijgen-Obregoso Real, A.,Blokland, S.,Garg, D.,Yu, W.,Goutier, W.,Lanckacker, E.,Klap, J.M.,Peeters, D.C.G.,Wu, J.,Buyck, C.,Jonckers, T.H.M.,Roymans, D.,Roevens, P.,Vogels, R.,Koudstaal, W.,Friesen, R.H.E.,Raboisson, P.,Dhanak, D.,Goudsmit, J.,Wilson, I.A.
A small-molecule fusion inhibitor of influenza virus is orally active in mice.
Science, 363:-, 2019

PubMed 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.

PubMed: 30846569
DOI: 10.1126/science.aar6221

Experimental method

X-RAY DIFFRACTION (2.719 Å)