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-Structure paper
タイトル | Neutralization of SARS-CoV-2 by highly potent, hyperthermostable, and mutation-tolerant nanobodies. |
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ジャーナル・号・ページ | EMBO J, Vol. 40, Issue 19, Page e107985, Year 2021 |
掲載日 | 2021年10月1日 |
著者 | Thomas Güttler / Metin Aksu / Antje Dickmanns / Kim M Stegmann / Kathrin Gregor / Renate Rees / Waltraud Taxer / Oleh Rymarenko / Jürgen Schünemann / Christian Dienemann / Philip Gunkel / Bianka Mussil / Jens Krull / Ulrike Teichmann / Uwe Groß / Volker C Cordes / Matthias Dobbelstein / Dirk Görlich / |
PubMed 要旨 | Monoclonal anti-SARS-CoV-2 immunoglobulins represent a treatment option for COVID-19. However, their production in mammalian cells is not scalable to meet the global demand. Single-domain (VHH) ...Monoclonal anti-SARS-CoV-2 immunoglobulins represent a treatment option for COVID-19. However, their production in mammalian cells is not scalable to meet the global demand. Single-domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. Using alpaca immune libraries against the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein, we isolated 45 infection-blocking VHH antibodies. These include nanobodies that can withstand 95°C. The most effective VHH antibody neutralizes SARS-CoV-2 at 17-50 pM concentration (0.2-0.7 µg per liter), binds the open and closed states of the Spike, and shows a tight RBD interaction in the X-ray and cryo-EM structures. The best VHH trimers neutralize even at 40 ng per liter. We constructed nanobody tandems and identified nanobody monomers that tolerate the K417N/T, E484K, N501Y, and L452R immune-escape mutations found in the Alpha, Beta, Gamma, Epsilon, Iota, and Delta/Kappa lineages. We also demonstrate neutralization of the Beta strain at low-picomolar VHH concentrations. We further discovered VHH antibodies that enforce native folding of the RBD in the E. coli cytosol, where its folding normally fails. Such "fold-promoting" nanobodies may allow for simplified production of vaccines and their adaptation to viral escape-mutations. |
リンク | EMBO J / PubMed:34302370 / PubMed Central |
手法 | EM (単粒子) / X線回折 |
解像度 | 1.25 - 3.5 Å |
構造データ | EMDB-13105: EMDB-13106: EMDB-13107: PDB-7olz: PDB-7on5: |
化合物 | ChemComp-DMX: ChemComp-SO4: ChemComp-HOH: ChemComp-EDO: ChemComp-EOH: |
由来 |
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キーワード | VIRAL PROTEIN / COVID19 / Neutralizing VHH / IMMUNE SYSTEM |