Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Case, James Brett; Chen, Rita E.; Cao, Longxing; Ying, Boaling; Winkler, Emma S.; Goreshnik, Inna; Shrihari, Swathi; Kafai, Natasha M.; Bailey, Adam L.; Xie, Xuping; Shi, Pei–Yong; Ravichandran, Rashmi; Carter, Lauren; Stewart, Lance; Baker, David; Diamond, Michael S.

doi:10.1101/2021.03.01.433110

Cited by 4 publications

(3 citation statements)

References 43 publications

(44 reference statements)

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“…A single nasal dose also reduced infection in the lung even when given as many as 5 days before or 2 days after virus inoculation. Importantly, the protein was demonstrated to protect animals against a historical strain (WA1/2020), an emerging B.1.1.7 variant, and a variant encoding key E484K and N501Y spike protein mutations [ 57 ]. These data support development of such antiviral miniproteins for prevention or treatment of COVID-19.…”

Section: Emerging Targets Emerging Modalitiesmentioning

confidence: 99%

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

Hall

Anderson

et al. 2021

The Journal of Infectious Diseases

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The NIH Virtual SARS-CoV-2 Antiviral Summit, held on November 6, 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for COVID-19, including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss SARS-CoV-2 targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.

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Section: Emerging Targets Emerging Modalitiesmentioning

confidence: 99%

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

Hall

Anderson

et al. 2021

The Journal of Infectious Diseases

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“…An alternative approach to the problem of short serum half-life is to avoid systemic administration altogether. This has been demonstrated through the generation of small ACE2 derived “miniproteins” which may be administered intranasally allowing access to the lung, a major site of COVID-19 pathogenesis (L. Y. Cao et al, 2020 ; Case et al, 2021 ). Sole use of inhalational therapeutics however will not address the multiorgan tropism of SARS-CoV-2 and the use of truncated ACE2 peptides may allow future mutational escape.…”

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confidence: 99%

A tetrameric ACE2 protein broadly neutralizes SARS-CoV-2 spike variants of concern with elevated potency

et al. 2021

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The SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) was previously engineered into a high affinity tetravalent format (ACE2-Fc-TD) that is a potential decoy protein in SARS-CoV-2 infection.We report that this protein shows greatly enhanced binding to SARS-CoV-2 spike proteins of the SARS-CoV-2 variants of concern B.1.1.7 (alpha variant, originally isolated in the United Kingdom) and B.1.351 (beta variant, originally isolated in South Africa) with picomolar compared with nanomolar Kd values. In addition, ACE2-Fc-TD displays greater neutralization of SARS-CoV-2 pseudotype viruses compared to a dimeric ACE2-Fc, with enhanced activity on variant B.1.351. This tetrameric decoy protein would be a valuable addition to SARS-CoV-2 therapeutic approaches, especially where vaccination cannot be used but also should there be any future coronavirus pandemics.

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“…With the outbreak of the SARS-CoV-2 coronavirus pandemic we applied our method to design miniproteins targeting the receptor binding domain of the SARS-CoV-2 Spike protein near the ACE2 binding site to block receptor engagement. Due to the pressing need for coronavirus therapeutics, we recently described the results of these efforts 37 ahead of those described in this manuscript; As in the case of FGFR2, IL-7Rα and VirB8, the method yielded picomolar binders, which are among the most potent compounds known to inhibit the virus in cell culture (IC50 0.15ng/ml) and subsequent animal experiments have shown that they provide potent protection against the virus in vivo 38 . The modular nature of the miniprotein binders enables their rapid integration into designed diagnostic biosensors for both influenza and SARS-CoV-2 binders 39 .…”

Section: )mentioning

confidence: 99%

Robust de novo design of protein binding proteins from target structural information alone

Cao

Coventry

Goreshnik

et al. 2021

Preprint

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The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge. We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes and interactions, and then intensifies the search in the most promising regions. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of four of the binder-target complexes, and all four are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.

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Ultrapotent miniproteins targeting the receptor-binding domain protect against SARS-CoV-2 infection and disease in mice

Cited by 4 publications

References 43 publications

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

A tetrameric ACE2 protein broadly neutralizes SARS-CoV-2 spike variants of concern with elevated potency

Robust de novo design of protein binding proteins from target structural information alone

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