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Multivalent designed proteins protect against SARS-CoV-2 variants of concern.

ABSTRACT: Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron microscopy (cryoEM) showed that these trivalent minibinders engage all three receptor binding domains on a single S trimer. The top candidates neutralize SARS-CoV-2 variants of concern with IC ₅₀ values in the low pM range, resist viral escape, and provide protection in highly vulnerable human ACE2-expressing transgenic mice, both prophylactically and therapeutically. Our integrated workflow promises to accelerate the design of mutationally resilient therapeutics for pandemic preparedness.

One-sentence summary

We designed, developed, and characterized potent, trivalent miniprotein binders that provide prophylactic and therapeutic protection against emerging SARS-CoV-2 variants of concern.

SUBMITTER: Hunt AC

PROVIDER: S-EPMC8282097 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Multivalent designed proteins protect against SARS-CoV-2 variants of concern.

Hunt Andrew C AC Case James Brett JB Park Young-Jun YJ Cao Longxing L Wu Kejia K Walls Alexandra C AC Liu Zhuoming Z Bowen John E JE Yeh Hsien-Wei HW Saini Shally S Helms Louisa L Zhao Yan Ting YT Hsiang Tien-Ying TY Starr Tyler N TN Goreshnik Inna I Kozodoy Lisa L Carter Lauren L Ravichandran Rashmi R Green Lydia B LB Matochko Wadim L WL Thomson Christy A CA Vögeli Bastain B Krüger-Gericke Antje A VanBlargan Laura A LA Chen Rita E RE Ying Baoling B Bailey Adam L AL Kafai Natasha M NM Boyken Scott S Ljubetič Ajasja A Edman Natasha N Ueda George G Chow Cameron C Addetia Amin A Panpradist Nuttada N Gale Michael M Freedman Benjamin S BS Lutz Barry R BR Bloom Jesse D JD Ruohola-Baker Hannele H Whelan Sean P J SPJ Stewart Lance L Diamond Michael S MS Veesler David D Jewett Michael C MC Baker David D

bioRxiv : the preprint server for biology 20210707

Escape variants of SARS-CoV-2 are threatening to prolong the COVID-19 pandemic. To address this challenge, we developed multivalent protein-based minibinders as potential prophylactic and therapeutic agents. Homotrimers of single minibinders and fusions of three distinct minibinders were designed to geometrically match the SARS-CoV-2 spike (S) trimer architecture and were optimized by cell-free expression and found to exhibit virtually no measurable dissociation upon binding. Cryo-electron micro ...[more]

PMID: 34268509

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Project description:The ability of SARS-CoV-2 to evolve in response to selective pressures poses a challenge to vaccine and antiviral efficacy. The S1 subunit of the spike (S) protein contains the receptor-binding domain and is therefore under selective pressure to evade neutralizing antibodies elicited by vaccination or infection. In contrast, the S2 subunit of S is only transiently exposed after receptor binding, which makes it a less efficient target for antibodies. As a result, S2 has a lower mutational frequency than S1. We recently described monomeric and dimeric SARS-CoV-2 fusion-inhibitory lipopeptides that block viral infection by interfering with S2 conformational rearrangements during viral entry. Importantly, a dimeric lipopeptide was shown to block SARS-CoV-2 transmission between ferrets in vivo. Because the S2 subunit is relatively conserved in newly emerging SARS-CoV-2 variants of concern (VOCs), we hypothesize that fusion-inhibitory lipopeptides are cross-protective against infection with VOCs. Here, we directly compared the in vitro efficacies of two fusion-inhibitory lipopeptides against VOC, in comparison with a set of seven postvaccination sera (two doses) and a commercial monoclonal antibody preparation. For the beta, delta, and omicron VOCs, it has been reported that convalescent and postvaccination sera are less potent in virus neutralization assays. Both fusion-inhibitory lipopeptides were equally effective against all five VOCs compared to ancestral virus, whereas postvaccination sera and therapeutic monoclonal antibody lost potency to newer VOCs, in particular to omicron BA.1 and BA.2. The neutralizing activity of the lipopeptides is consistent, and they can be expected to neutralize future VOCs based on their mechanism of action. IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, continues to spread globally, with waves resulting from new variants that evade immunity generated by vaccines and previous strains and escape available monoclonal antibody therapy. Fusion-inhibitory peptides may provide an intervention strategy that is not similarly affected by this viral evolution.

Dataset Information

Multivalent designed proteins protect against SARS-CoV-2 variants of concern.

One-sentence summary

Publications

Multivalent designed proteins protect against SARS-CoV-2 variants of concern.

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