Thread by @veeslerlab

We characterized the structural basis of #SARSCoV2 #OmicronVariant binding to the host ACE2 receptor and neutralization by the S309/sotrovimab clinical antibody therapeutic!

Led by @Dr_MattMcCallum & Nadine Czudnochowski Collab w Gyorgy Snell

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biorxiv.org/content/10.110…

We show that the #OmicronVariant spike NTD antigenic supersite is structurally rearranged, relative to the Wuhan-Hu-1 NTD, explaining the loss of binding and neutralization by a panel of NTD-targeted monoclonal antibodies we recently evaluated (nature.com/articles/d4158…).

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The #OmicronVariant spike S2 subunit (fusion machinery) harbors mutations introducing additional electrostatic contacts with the S1 subunit, which might explain the reduced S1 shedding described in this preprint (biorxiv.org/content/10.110…)

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Reduced S1/S2 cleavage shown in this preprint (biorxiv.org/content/10.110…) from @GuptaR_lab likely also participates in limiting S1 shedding which might enhance the Fc-mediated effector functions of some antibodies

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We provide a blueprint of the #OmicronVariant spike RBD mutations explaining the marked dampening of binding of all therapeutic mAbs, leading to reduced neutralizing activity, except for S309/sotrovimab that has 2-3x reduced binding/neutralization

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Finally, we reveal a remodeling of (electrostatic) interactions with human ACE2 due to K417N, S477N, Q493R, Q498R & N501Y explaining enhanced receptor binding relative to Wuhan-Hu-1.

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This work provides a structural framework to understand broad evasion of humoral immunity and underscores the #SARSCoV2 spike mutational plasticity and the importance of targeting conserved epitopes for vaccine and therapeutics design.

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Thank you so much to @SamK_Zepeda @johnbowenbio and our fantastic collaborators including @DavideCorti6

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