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  1. Article ; Online: Avidity engineering of human heavy-chain-only antibodies mitigates neutralization resistance of SARS-CoV-2 variants.

    Du, Wenjuan / Janssens, Rick / Mykytyn, Anna Z / Li, Wentao / Drabek, Dubravka / van Haperen, Rien / Chatziandreou, Marianthi / Rissmann, Melanie / van der Lee, Joline / van Dortmondt, Melissa / Martin, Itziar Serna / van Kuppeveld, Frank J M / Hurdiss, Daniel L / Haagmans, Bart L / Grosveld, Frank / Bosch, Berend-Jan

    Frontiers in immunology

    2023  Volume 14, Page(s) 1111385

    Abstract: Emerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more ... ...

    Abstract Emerging SARS-CoV-2 variants have accrued mutations within the spike protein rendering most therapeutic monoclonal antibodies against COVID-19 ineffective. Hence there is an unmet need for broad-spectrum mAb treatments for COVID-19 that are more resistant to antigenically drifted SARS-CoV-2 variants. Here we describe the design of a biparatopic heavy-chain-only antibody consisting of six antigen binding sites recognizing two distinct epitopes in the spike protein NTD and RBD. The hexavalent antibody showed potent neutralizing activity against SARS-CoV-2 and variants of concern, including the Omicron sub-lineages BA.1, BA.2, BA.4 and BA.5, whereas the parental components had lost Omicron neutralization potency. We demonstrate that the tethered design mitigates the substantial decrease in spike trimer affinity seen for escape mutations for the hexamer components. The hexavalent antibody protected against SARS-CoV-2 infection in a hamster model. This work provides a framework for designing therapeutic antibodies to overcome antibody neutralization escape of emerging SARS-CoV-2 variants.
    MeSH term(s) Animals ; Cricetinae ; Humans ; SARS-CoV-2/genetics ; COVID-19 ; Spike Glycoprotein, Coronavirus/genetics ; Immunoglobulin Heavy Chains/genetics ; Antibodies, Monoclonal
    Chemical Substances Spike Glycoprotein, Coronavirus ; Immunoglobulin Heavy Chains ; Antibodies, Monoclonal ; spike protein, SARS-CoV-2
    Language English
    Publishing date 2023-02-21
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1111385
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Flavivirus maturation leads to the formation of an occupied lipid pocket in the surface glycoproteins.

    Renner, Max / Dejnirattisai, Wanwisa / Carrique, Loïc / Martin, Itziar Serna / Karia, Dimple / Ilca, Serban L / Ho, Shu F / Kotecha, Abhay / Keown, Jeremy R / Mongkolsapaya, Juthathip / Screaton, Gavin R / Grimes, Jonathan M

    Nature communications

    2021  Volume 12, Issue 1, Page(s) 1238

    Abstract: Flaviviruses such as Dengue (DENV) or Zika virus (ZIKV) assemble into an immature form within the endoplasmatic reticulum (ER), and are then processed by furin protease in the trans-Golgi. To better grasp maturation, we carry out cryo-EM reconstructions ... ...

    Abstract Flaviviruses such as Dengue (DENV) or Zika virus (ZIKV) assemble into an immature form within the endoplasmatic reticulum (ER), and are then processed by furin protease in the trans-Golgi. To better grasp maturation, we carry out cryo-EM reconstructions of immature Spondweni virus (SPOV), a human flavivirus of the same serogroup as ZIKV. By employing asymmetric localised reconstruction we push the resolution to 3.8 Å, enabling us to refine an atomic model which includes the crucial furin protease recognition site and a conserved Histidine pH-sensor. For direct comparison, we also solve structures of the mature forms of SPONV and DENV to 2.6 Å and 3.1 Å, respectively. We identify an ordered lipid that is present in only the mature forms of ZIKV, SPOV, and DENV and can bind as a consequence of rearranging amphipathic stem-helices of E during maturation. We propose a structural role for the pocket and suggest it stabilizes mature E.
    MeSH term(s) Amino Acid Sequence ; Flavivirus/physiology ; Flavivirus/ultrastructure ; Lipids/chemistry ; Membrane Glycoproteins/chemistry ; Models, Molecular ; Protein Structure, Secondary
    Chemical Substances Lipids ; Membrane Glycoproteins
    Language English
    Publishing date 2021-02-23
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-021-21505-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Author Correction: GABA

    Masiulis, Simonas / Desai, Rooma / Uchański, Tomasz / Martin, Itziar Serna / Laverty, Duncan / Karia, Dimple / Malinauskas, Tomas / Zivanov, Jasenko / Pardon, Els / Kotecha, Abhay / Steyaert, Jan / Miller, Keith W / Aricescu, A Radu

    Nature

    2019  Volume 566, Issue 7744, Page(s) E8

    Abstract: In Fig. 5b, d, the arrows showing transmembrane domain rotations were inadvertently pointing clockwise instead of anticlockwise. Similarly, 'anticlockwise' should have been 'clockwise' in the sentence 'This conformational change of the ECD triggers a ... ...

    Abstract In Fig. 5b, d, the arrows showing transmembrane domain rotations were inadvertently pointing clockwise instead of anticlockwise. Similarly, 'anticlockwise' should have been 'clockwise' in the sentence 'This conformational change of the ECD triggers a clockwise rotation of the TMD.' In Extended Data Table 1, the units of the column 'Model resolution' should have been Å instead of Å
    Language English
    Publishing date 2019-02-01
    Publishing country England
    Document type Journal Article ; Published Erratum
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-019-0929-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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