6cf7
Crystal structure of the A/Solomon Islands/3/2006(H1N1) influenza virus hemagglutinin in complex with small molecule JNJ4796
Structural highlights
FunctionA7Y8I1_9INFA Binds to sialic acid-containing receptors on the cell surface, bringing about the attachment of the virus particle to the cell. This attachment induces virion internalization either through clathrin-dependent endocytosis or through clathrin- and caveolin-independent pathway. Plays a major role in the determination of host range restriction and virulence. Class I viral fusion protein. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in HA2, releasing the fusion hydrophobic peptide. Several trimers are required to form a competent fusion pore.[HAMAP-Rule:MF_04072][SAAS:SAAS01039073] Binds to sialic acid-containing receptors on the cell surface, bringing about the attachment of the virus particle to the cell. This attachment induces virion internalization of about two third of the virus particles through clathrin-dependent endocytosis and about one third through a clathrin- and caveolin-independent pathway. Plays a major role in the determination of host range restriction and virulence. Class I viral fusion protein. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in HA2, releasing the fusion hydrophobic peptide. Several trimers are required to form a competent fusion pore.[RuleBase:RU003324] Publication Abstract from PubMedRecent 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. A small-molecule fusion inhibitor of influenza virus is orally active in mice.,van Dongen MJP, Kadam RU, Juraszek J, Lawson E, Brandenburg B, Schmitz F, Schepens WBG, Stoops B, van Diepen HA, Jongeneelen M, Tang C, Vermond J, van Eijgen-Obregoso Real A, Blokland S, Garg D, Yu W, Goutier W, Lanckacker E, Klap JM, Peeters DCG, Wu J, Buyck C, Jonckers THM, Roymans D, Roevens P, Vogels R, Koudstaal W, Friesen RHE, Raboisson P, Dhanak D, Goudsmit J, Wilson IA Science. 2019 Mar 8;363(6431). pii: 363/6431/eaar6221. doi:, 10.1126/science.aar6221. PMID:30846569[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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