De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

Abstract

A decoy to neutralize SARS-CoV-2 Many efforts to develop therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are focused on the interaction between the spike protein, which decorates the surface of the virus, and its host receptor, human angiotensin-converting enzyme 2 (hACE2). Linsky et al. describe a de novo design strategy that allowed them to engineer decoy proteins that bind to the spike protein by replicating the hACE2 interface. The best decoy, CTC-445, bound with low nanomolar affinity, and selection of viral mutants that decrease binding is unlikely because this would also affect binding to hACE2. A bivalent version of CTC-445 bound even more tightly, neutralized SARS-CoV-2 infection of cells, and protected hamsters from a SARS-CoV-2 challenge. The stable decoy has the potential for respiratory therapeutic delivery. Science , this issue p. 1208

References 67

1. 1.

   D. E. Gordon, G. M. Jang, M. Bouhaddou, J. Xu, K. Obernier, K. M. White, M. J. O’Meara, V. V. Rezelj, J. Z. Guo, D. L. Swaney, T. A. Tummino, R. Hüttenhain, R. M. Kaake, A. L. Richards, B. Tutuncuoglu, H. Foussard, J. Batra, K. Haas, M. Modak, M. Kim, P. Haas, B. J. Polacco, H. Braberg, J. M. Fabius, M. Eckhardt, M. Soucheray, M. J. Bennett, M. Cakir, M. J. McGregor, Q. Li, B. Meyer, F. Roesch, T. Vallet, A. Mac Kain, L. Miorin, E. Moreno, Z. Z. C. Naing, Y. Zhou, S. Peng, Y. Shi, Z. Zhang, W. Shen, I. T. Kirby, J. E. Melnyk, J. S. Chorba, K. Lou, S. A. Dai, I. Barrio-Hernandez, D. Memon, C. Hernandez-Armenta, J. Lyu, C. J. P. Mathy, T. Perica, K. B. Pilla, S. J. Ganesan, D. J. Saltzberg, R. Rakesh, X. Liu, S. B. Rosenthal, L. Calviello, S. Venkataramanan, J. Liboy-Lugo, Y. Lin, X.-P. Huang, Y. Liu, S. A. Wankowicz, M. Bohn, M. Safari, F. S. Ugur, C. Koh, N. S. Savar, Q. D. Tran, D. Shengjuler, S. J. Fletcher, M. C. O’Neal, Y. Cai, J. C. J. Chang, D. J. Broadhurst, S. Klippsten, P. P. Sharp, N. A. Wenzell, D. Kuzuoglu-Ozturk, H.-Y. Wang, R. Trenker, J. M. Young, D. A. Cavero, J. Hiatt, T. L. Roth, U. Rathore, A. Subramanian, J. Noack, M. Hubert, R. M. Stroud, A. D. Frankel, O. S. Rosenberg, K. A. Verba, D. A. Agard, M. Ott, M. Emerman, N. Jura, M. von Zastrow, E. Verdin, A. Ashworth, O. Schwartz, C. d’Enfert, S. Mukherjee, M. Jacobson, H. S. Malik, D. G. Fujimori, T. Ideker, C. S. Craik, S. N. Floor, J. S. Fraser, J. D. Gross, A. Sali, B. L. Roth, D. Ruggero, J. Taunton, T. Kortemme, P. Beltrao, M. Vignuzzi, A. García-Sastre, K. M. Shokat, B. K. Shoichet, N. J. Krogan, A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 583, 459–468 (2020 ).

   Not in our library10.1038/s41586-020-2286-9

2. 2.

   C. Liu, Q. Zhou, Y. Li, L. V. Garner, S. P. Watkins, L. J. Carter, J. Smoot, A. C. Gregg, A. D. Daniels, S. Jervey, D. Albaiu, Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases. ACS Cent. Sci. 6, 315–331 (2020 ).

   Not in our library10.1021/acscentsci.0c00272

3. 3.

   W.-H. Chen, U. Strych, P. J. Hotez, M. E. Bottazzi, The SARS-CoV-2 vaccine pipeline: An overview. Curr. Trop. Med. Rep. 7, 1–4 (2020 ).

   Not in our library10.1007/s40475-020-00201-6

4. 4.
   Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2 · 2020

   No notice
5. 5.

   J. D. Walter, C. A. J. Hutter, I. Zimmermann, J. Earp, P. Egloff, M. Sorgenfrei, L. M. Hürlimann, I. Gonda, G. Meier, S. Remm, S. Thavarasah, P. Plattet, M. A. Seeger, Sybodies targeting the SARS-CoV-2 receptor-binding domain. bioRxiv 045419 [Preprint]. 16 May 2020..

   Not in our library10.1101/2020.04.16.045419

6. 6.
   De novo design of picomolar SARS-CoV-2 miniprotein inhibitors · 2020

   No notice
7. 7.
   Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors · 2020

   No notice
8. 8.

   E. C. Smith, M. R. Denison, Coronaviruses as DNA wannabes: A new model for the regulation of RNA virus replication fidelity. PLOS Pathog. 9, e1003760 (2013 ).

   Not in our library10.1371/journal.ppat.1003760

9. 9.
   Why are RNA virus mutation rates so damn high? · 2018

   No notice
10. 10.

    Z. Zhao, H. Li, X. Wu, Y. Zhong, K. Zhang, Y.-P. Zhang, E. Boerwinkle, Y.-X. Fu, Moderate mutation rate in the SARS coronavirus genome and its implications. BMC Evol. Biol. 4, 21 (2004 ).

    Not in our library10.1186/1471-2148-4-21

11. 11.
    Complete mapping of viral escape from neutralizing antibodies · 2017

    No notice
12. 12.

    T. Phan, Genetic diversity and evolution of SARS-CoV-2. Infect. Genet. Evol. 81, 104260 (2020 ).

    Not in our library10.1016/j.meegid.2020.104260

13. 13.

    J. Hu, C.-L. He, Q.-Z. Gao, G.-J. Zhang, X.-X. Cao, Q.-X. Long, H.-J. Deng, L.-Y. Huang, J. Chen, K. Wang, N. Tang, A.-L. Huang, D614G mutation of SARS-CoV-2 spike protein enhances viral infectivity. bioRxiv 161323 [Preprint]. 6 July 2020..

    Not in our library10.1101/2020.06.20.161323

14. 14.
    Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies · 2020

    No notice
15. 15.
    Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding · 2020

    No notice
16. 16.
    Human Monoclonal Antibody Combination against SARS Coronavirus: Synergy and Coverage of Escape Mutants · 2006

    No notice
17. 17.

    L. Enjuanes, S. Zuñiga, C. Castano-Rodriguez, J. Gutierrez-Alvarez, J. Canton, I. Sola, “Molecular basis of coronavirus virulence and vaccine development,” in Advances in Virus Research, J. Ziebuhr, Ed. (Elsevier, 2016), vol. 96, pp. 245–286.

    Not in our library10.1016/bs.aivir.2016.08.003

18. 18.

    S. Belouzard, V. C. Chu, G. R. Whittaker, Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc. Natl. Acad. Sci. U.S.A. 106, 5871–5876 (2009 ).

    Not in our library10.1073/pnas.0809524106

19. 19.
    Cell entry mechanisms of SARS-CoV-2 · 2020

    No notice
20. 20.

    J. K. Millet, G. R. Whittaker, Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc. Natl. Acad. Sci. U.S.A. 111, 15214–15219 (2014 ).

    Not in our library10.1073/pnas.1407087111

21. 21.
    Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV · 2020

    Corrected
22. 22.
    From SARS to MERS, Thrusting Coronaviruses into the Spotlight · 2019

    No notice
23. 23.
    Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2 · 2020

    No notice
24. 24.

    Q. Wang, Y. Zhang, L. Wu, S. Niu, C. Song, Z. Zhang, G. Lu, C. Qiao, Y. Hu, K.-Y. Yuen, Q. Wang, H. Zhou, J. Yan, J. Qi, Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181, 894–904.e9 (2020 ).

    Not in our library10.1016/j.cell.2020.03.045

25. 25.

    J. Lan, J. Ge, J. Yu, S. Shan, H. Zhou, S. Fan, Q. Zhang, X. Shi, Q. Wang, L. Zhang, X. Wang, Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581, 215–220 (2020 ).

    Not in our library10.1038/s41586-020-2180-5

26. 26.

    D.-A. Silva, S. Yu, U. Y. Ulge, J. B. Spangler, K. M. Jude, C. Labão-Almeida, L. R. Ali, A. Quijano-Rubio, M. Ruterbusch, I. Leung, T. Biary, S. J. Crowley, E. Marcos, C. D. Walkey, B. D. Weitzner, F. Pardo-Avila, J. Castellanos, L. Carter, L. Stewart, S. R. Riddell, M. Pepper, G. J. L. Bernardes, M. Dougan, K. C. Garcia, D. Baker, De novo design of potent and selective mimics of IL-2 and IL-15. Nature 565, 186–191 (2019 ).

    Not in our library10.1038/s41586-018-0830-7

27. 27.

    F. Sesterhenn, C. Yang, J. Bonet, J. T. Cramer, X. Wen, Y. Wang, C.-I. Chiang, L. A. Abriata, I. Kucharska, G. Castoro, S. S. Vollers, M. Galloux, E. Dheilly, S. Rosset, P. Corthésy, S. Georgeon, M. Villard, C.-A. Richard, D. Descamps, T. Delgado, E. Oricchio, M.-A. Rameix-Welti, V. Más, S. Ervin, J.-F. Eléouët, S. Riffault, J. T. Bates, J.-P. Julien, Y. Li, T. Jardetzky, T. Krey, B. E. Correia, De novo protein design enables the precise induction of RSV-neutralizing antibodies. Science 368, eaay5051 (2020 ).

    Not in our library10.1126/science.aay5051

28. 28.

    J. Zhou, A. E. Panaitiu, G. Grigoryan, A general-purpose protein design framework based on mining sequence-structure relationships in known protein structures. Proc. Natl. Acad. Sci. U.S.A. 117, 1059–1068 (2020 ).

    Not in our library10.1073/pnas.1908723117

29. 29.

    D.-A. Silva, B. E. Correia, E. Procko, “Motif-driven design of protein–protein interfaces,” in Computational Design of Ligand Binding Proteins, B. L. Stoddard, Ed. (Humana, 2016), vol. 1414, pp. 285–304.

    Not in our library10.1007/978-1-4939-3569-7_17

30. 30.

    A. Quijano-Rubio, U. Y. Ulge, C. D. Walkey, D.-A. Silva, The advent of de novo proteins for cancer immunotherapy. Curr. Opin. Chem. Biol. 56, 119–128 (2020 ).

    Not in our library10.1016/j.cbpa.2020.02.002

31. 31.

    A. Leaver-Fay, M. Tyka, S. M. Lewis, O. F. Lange, J. Thompson, R. Jacak, K. Kaufman, P. D. Renfrew, C. A. Smith, W. Sheffler, I. W. Davis, S. Cooper, A. Treuille, D. J. Mandell, F. Richter, Y.-E. A. Ban, S. J. Fleishman, J. E. Corn, D. E. Kim, S. Lyskov, M. Berrondo, S. Mentzer, Z. Popović, J. J. Havranek, J. Karanicolas, R. Das, J. Meiler, T. Kortemme, J. J. Gray, B. Kuhlman, D. Baker, P. Bradley, ROSETTA3: An object-oriented software suite for the simulation and design of macromolecules. Methods Enzymol. 487, 545–574 (2011 ).

    Not in our library10.1016/b978-0-12-381270-4.00019-6

32. 32.

    E. Marcos, D.-A. Silva, Essentials of de novo protein design: Methods and applications. WIREs Comput Mol Sci 8, e1374 (2018 ).

    Not in our library10.1002/wcms.1374

33. 33.

    A. Chevalier, D.-A. Silva, G. J. Rocklin, D. R. Hicks, R. Vergara, P. Murapa, S. M. Bernard, L. Zhang, K.-H. Lam, G. Yao, C. D. Bahl, S.-I. Miyashita, I. Goreshnik, J. T. Fuller, M. T. Koday, C. M. Jenkins, T. Colvin, L. Carter, A. Bohn, C. M. Bryan, D. A. Fernández-Velasco, L. Stewart, M. Dong, X. Huang, R. Jin, I. A. Wilson, D. H. Fuller, D. Baker, Massively parallel de novo protein design for targeted therapeutics. Nature 550, 74–79 (2017 ).

    Not in our library10.1038/nature23912

34. 34.

    T. A. Whitehead, A. Chevalier, Y. Song, C. Dreyfus, S. J. Fleishman, C. De Mattos, C. A. Myers, H. Kamisetty, P. Blair, I. A. Wilson, D. Baker, Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. Nat. Biotechnol. 30, 543–548 (2012 ).

    Not in our library10.1038/nbt.2214

35. 35.

    M. Hoffmann, H. Kleine-Weber, S. Schroeder, N. Krüger, T. Herrler, S. Erichsen, T. S. Schiergens, G. Herrler, N.-H. Wu, A. Nitsche, M. A. Müller, C. Drosten, S. Pöhlmann, SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280.e8 (2020 ).

    Not in our library10.1016/j.cell.2020.02.052

36. 36.

    W. Sungnak, N. Huang, C. Bécavin, M. Berg, R. Queen, M. Litvinukova, C. Talavera-López, H. Maatz, D. Reichart, F. Sampaziotis, K. B. Worlock, M. Yoshida, J. L. Barnes; HCA Lung Biological Network, SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat. Med. 26, 681–687 (2020 ).

    Not in our library10.1038/s41591-020-0868-6

37. 37.

    M. P. Baker, H. M. Reynolds, B. Lumicisi, C. J. Bryson, Immunogenicity of protein therapeutics: The key causes, consequences and challenges. Self Nonself 1, 314–322 (2010 ).

    Not in our library10.4161/self.1.4.13904

38. 38.

    N. Casadevall, J. Nataf, B. Viron, A. Kolta, J.-J. Kiladjian, P. Martin-Dupont, P. Michaud, T. Papo, V. Ugo, I. Teyssandier, B. Varet, P. Mayeux, Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346, 469–475 (2002 ).

    Not in our library10.1056/nejmoa011931

39. 39.

    M. G. Tovey, C. Lallemand, Immunogenicity and other problems associated with the use of biopharmaceuticals. Ther. Adv. Drug Saf. 2, 113–128 (2011 ).

    Not in our library10.1177/2042098611406318

40. 40.

    J. Li, C. Yang, Y. Xia, A. Bertino, J. Glaspy, M. Roberts, D. J. Kuter, Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98, 3241–3248 (2001 ).

    Not in our library10.1182/blood.v98.12.3241

Cited by papers we hold 3

• Scaffolding protein functional sites using deep learning · 2022
  No notice
• Circulating ACE2-expressing extracellular vesicles block broad strains of SARS-CoV-2 · 2022
  No notice
• Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19 · 2020
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.