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Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape.

ABSTRACT: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.

SUBMITTER: Koenig PA

PROVIDER: S-EPMC7932109 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape.

Koenig Paul-Albert PA Das Hrishikesh H Liu Hejun H Kümmerer Beate M BM Gohr Florian N FN Jenster Lea-Marie LM Schiffelers Lisa D J LDJ Tesfamariam Yonas M YM Uchima Miki M Wuerth Jennifer D JD Gatterdam Karl K Ruetalo Natalia N Christensen Maria H MH Fandrey Caroline I CI Normann Sabine S Tödtmann Jan M P JMP Pritzl Steffen S Hanke Leo L Boos Jannik J Yuan Meng M Zhu Xueyong X Schmid-Burgk Jonathan L JL Kato Hiroki H Schindler Michael M Wilson Ian A IA Geyer Matthias M Ludwig Kerstin U KU Hällberg B Martin BM Wu Nicholas C NC Schmidt Florian I FI

Science (New York, N.Y.) 20210112 6530

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structu ...[more]

PMID: 33436526

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Project description:Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric determinants of the SARS-CoV-2 spike protein binding with nanobodies, we also examined nanobody-induced modulation of escaping mutations and the effect of the Omicron variant on nanobody binding. The mutational scanning analysis supported the notion that E484A mutation can have a significant detrimental effect on nanobody binding and result in Omicron-induced escape from nanobody neutralization. Our findings showed that SARS-CoV-2 spike protein might exploit the plasticity of specific allosteric hotspots to generate escape mutants that alter response to binding without compromising activity. The network analysis supported these findings showing that VHH E/VHH V nanobody binding can induce long-range couplings between the cryptic binding epitope and ACE2-binding site through a broader ensemble of communication paths that is less dependent on specific mediating centers and therefore may be less sensitive to mutational perturbations of functional residues. The results suggest that binding affinity and long-range communications of the SARS-CoV-2 complexes with nanobodies can be determined by structurally stable regulatory centers and conformationally adaptable hotspots that are allosterically coupled and collectively control resilience to mutational escape.

Dataset Information

Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape.

Publications

Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape.

Similar Datasets

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