IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37786-1.html
   My bibliography  Save this article

High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike

Author

Listed:
  • Timothy J. C. Tan

    (University of Illinois Urbana-Champaign)

  • Zongjun Mou

    (Case Western Reserve University School of Medicine)

  • Ruipeng Lei

    (University of Illinois Urbana-Champaign)

  • Wenhao O. Ouyang

    (University of Illinois Urbana-Champaign)

  • Meng Yuan

    (The Scripps Research Institute)

  • Ge Song

    (The Scripps Research Institute
    The Scripps Research Institute
    The Scripps Research Institute)

  • Raiees Andrabi

    (The Scripps Research Institute
    The Scripps Research Institute
    The Scripps Research Institute)

  • Ian A. Wilson

    (The Scripps Research Institute
    The Scripps Research Institute
    The Scripps Research Institute
    The Scripps Research Institute)

  • Collin Kieffer

    (University of Illinois Urbana-Champaign)

  • Xinghong Dai

    (Case Western Reserve University School of Medicine)

  • Kenneth A. Matreyek

    (Case Western Reserve University School of Medicine)

  • Nicholas C. Wu

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

Abstract

Designing prefusion-stabilized SARS-CoV-2 spike is critical for the effectiveness of COVID-19 vaccines. All COVID-19 vaccines in the US encode spike with K986P/V987P mutations to stabilize its prefusion conformation. However, contemporary methods on engineering prefusion-stabilized spike immunogens involve tedious experimental work and heavily rely on structural information. Here, we establish a systematic and unbiased method of identifying mutations that concomitantly improve expression and stabilize the prefusion conformation of the SARS-CoV-2 spike. Our method integrates a fluorescence-based fusion assay, mammalian cell display technology, and deep mutational scanning. As a proof-of-concept, we apply this method to a region in the S2 domain that includes the first heptad repeat and central helix. Our results reveal that besides K986P and V987P, several mutations simultaneously improve expression and significantly lower the fusogenicity of the spike. As prefusion stabilization is a common challenge for viral immunogen design, this work will help accelerate vaccine development against different viruses.

Suggested Citation

  • Timothy J. C. Tan & Zongjun Mou & Ruipeng Lei & Wenhao O. Ouyang & Meng Yuan & Ge Song & Raiees Andrabi & Ian A. Wilson & Collin Kieffer & Xinghong Dai & Kenneth A. Matreyek & Nicholas C. Wu, 2023. "High-throughput identification of prefusion-stabilizing mutations in SARS-CoV-2 spike," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37786-1
    DOI: 10.1038/s41467-023-37786-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37786-1
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-37786-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Robert N. Kirchdoerfer & Christopher A. Cottrell & Nianshuang Wang & Jesper Pallesen & Hadi M. Yassine & Hannah L. Turner & Kizzmekia S. Corbett & Barney S. Graham & Jason S. McLellan & Andrew B. Ward, 2016. "Pre-fusion structure of a human coronavirus spike protein," Nature, Nature, vol. 531(7592), pages 118-121, March.
    2. Leopold Kong & Linling He & Natalia de Val & Nemil Vora & Charles D. Morris & Parisa Azadnia & Devin Sok & Bin Zhou & Dennis R. Burton & Andrew B. Ward & Ian A. Wilson & Jiang Zhu, 2016. "Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
    3. Jarek Juraszek & Lucy Rutten & Sven Blokland & Pascale Bouchier & Richard Voorzaat & Tina Ritschel & Mark J. G. Bakkers & Ludovic L. R. Renault & Johannes P. M. Langedijk, 2021. "Stabilizing the closed SARS-CoV-2 spike trimer," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    4. Lihong Liu & Pengfei Wang & Manoj S. Nair & Jian Yu & Micah Rapp & Qian Wang & Yang Luo & Jasper F.-W. Chan & Vincent Sahi & Amir Figueroa & Xinzheng V. Guo & Gabriele Cerutti & Jude Bimela & Jason Go, 2020. "Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike," Nature, Nature, vol. 584(7821), pages 450-456, August.
    5. Fan Wu & Su Zhao & Bin Yu & Yan-Mei Chen & Wen Wang & Zhi-Gang Song & Yi Hu & Zhao-Wu Tao & Jun-Hua Tian & Yuan-Yuan Pei & Ming-Li Yuan & Yu-Ling Zhang & Fa-Hui Dai & Yi Liu & Qi-Min Wang & Jiao-Jiao , 2020. "Author Correction: A new coronavirus associated with human respiratory disease in China," Nature, Nature, vol. 580(7803), pages 7-7, April.
    6. Peng Zhou & Xing-Lou Yang & Xian-Guang Wang & Ben Hu & Lei Zhang & Wei Zhang & Hao-Rui Si & Yan Zhu & Bei Li & Chao-Lin Huang & Hui-Dong Chen & Jing Chen & Yun Luo & Hua Guo & Ren-Di Jiang & Mei-Qin L, 2020. "Addendum: A pneumonia outbreak associated with a new coronavirus of probable bat origin," Nature, Nature, vol. 588(7836), pages 6-6, December.
    7. Jun Lan & Jiwan Ge & Jinfang Yu & Sisi Shan & Huan Zhou & Shilong Fan & Qi Zhang & Xuanling Shi & Qisheng Wang & Linqi Zhang & Xinquan Wang, 2020. "Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor," Nature, Nature, vol. 581(7807), pages 215-220, May.
    8. Mathieu Claireaux & Tom G. Caniels & Marlon Gast & Julianna Han & Denise Guerra & Gius Kerster & Barbera D. C. Schaik & Aldo Jongejan & Angela I. Schriek & Marloes Grobben & Philip J. M. Brouwer & Kar, 2022. "A public antibody class recognizes an S2 epitope exposed on open conformations of SARS-CoV-2 spike," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Peng Zhou & Xing-Lou Yang & Xian-Guang Wang & Ben Hu & Lei Zhang & Wei Zhang & Hao-Rui Si & Yan Zhu & Bei Li & Chao-Lin Huang & Hui-Dong Chen & Jing Chen & Yun Luo & Hua Guo & Ren-Di Jiang & Mei-Qin L, 2020. "A pneumonia outbreak associated with a new coronavirus of probable bat origin," Nature, Nature, vol. 579(7798), pages 270-273, March.
    10. Chunyan Wang & Rien Haperen & Javier Gutiérrez-Álvarez & Wentao Li & Nisreen M. A. Okba & Irina Albulescu & Ivy Widjaja & Brenda Dieren & Raul Fernandez-Delgado & Isabel Sola & Daniel L. Hurdiss & Ola, 2021. "A conserved immunogenic and vulnerable site on the coronavirus spike protein delineated by cross-reactive monoclonal antibodies," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    11. Christopher O. Barnes & Claudia A. Jette & Morgan E. Abernathy & Kim-Marie A. Dam & Shannon R. Esswein & Harry B. Gristick & Andrey G. Malyutin & Naima G. Sharaf & Kathryn E. Huey-Tubman & Yu E. Lee &, 2020. "SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies," Nature, Nature, vol. 588(7839), pages 682-687, December.
    12. Fan Wu & Su Zhao & Bin Yu & Yan-Mei Chen & Wen Wang & Zhi-Gang Song & Yi Hu & Zhao-Wu Tao & Jun-Hua Tian & Yuan-Yuan Pei & Ming-Li Yuan & Yu-Ling Zhang & Fa-Hui Dai & Yi Liu & Qi-Min Wang & Jiao-Jiao , 2020. "A new coronavirus associated with human respiratory disease in China," Nature, Nature, vol. 579(7798), pages 265-269, March.
    13. Florian Krammer, 2020. "SARS-CoV-2 vaccines in development," Nature, Nature, vol. 586(7830), pages 516-527, October.
    14. Bo Meng & Adam Abdullahi & Isabella A. T. M. Ferreira & Niluka Goonawardane & Akatsuki Saito & Izumi Kimura & Daichi Yamasoba & Pehuén Pereyra Gerber & Saman Fatihi & Surabhi Rathore & Samantha K. Zep, 2022. "Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity," Nature, Nature, vol. 603(7902), pages 706-714, March.
    15. Yuan Yuan & Duanfang Cao & Yanfang Zhang & Jun Ma & Jianxun Qi & Qihui Wang & Guangwen Lu & Ying Wu & Jinghua Yan & Yi Shi & Xinzheng Zhang & George F. Gao, 2017. "Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jing Wang & Yuan-fei Pan & Li-fen Yang & Wei-hong Yang & Kexin Lv & Chu-ming Luo & Juan Wang & Guo-peng Kuang & Wei-chen Wu & Qin-yu Gou & Gen-yang Xin & Bo Li & Huan-le Luo & Shoudeng Chen & Yue-long, 2023. "Individual bat virome analysis reveals co-infection and spillover among bats and virus zoonotic potential," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Peter Radvak & Hyung-Joon Kwon & Martina Kosikova & Uriel Ortega-Rodriguez & Ruoxuan Xiang & Je-Nie Phue & Rong-Fong Shen & James Rozzelle & Neeraj Kapoor & Taylor Rabara & Jeff Fairman & Hang Xie, 2021. "SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Xiaoming Hu & Shuang Wang & Shaotong Fu & Meng Qin & Chengliang Lyu & Zhaowen Ding & Yan Wang & Yishu Wang & Dongshu Wang & Li Zhu & Tao Jiang & Jing Sun & Hui Ding & Jie Wu & Lingqian Chang & Yimin C, 2023. "Intranasal mask for protecting the respiratory tract against viral aerosols," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    4. Phanramphoei N. Frantz & Aleksandr Barinov & Claude Ruffié & Chantal Combredet & Valérie Najburg & Guilherme Dias de Melo & Florence Larrous & Lauriane Kergoat & Samaporn Teeravechyan & Anan Jongkaeww, 2021. "A live measles-vectored COVID-19 vaccine induces strong immunity and protection from SARS-CoV-2 challenge in mice and hamsters," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    5. Wenjuan Du & Oliver Debski-Antoniak & Dubravka Drabek & Rien Haperen & Melissa Dortmondt & Joline Lee & Ieva Drulyte & Frank J. M. Kuppeveld & Frank Grosveld & Daniel L. Hurdiss & Berend-Jan Bosch, 2024. "Neutralizing antibodies reveal cryptic vulnerabilities and interdomain crosstalk in the porcine deltacoronavirus spike protein," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Hengrui Liu & Sho Iketani & Arie Zask & Nisha Khanizeman & Eva Bednarova & Farhad Forouhar & Brandon Fowler & Seo Jung Hong & Hiroshi Mohri & Manoj S. Nair & Yaoxing Huang & Nicholas E. S. Tay & Sumin, 2022. "Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Eugene Song & Jae-Eun Lee & Seola Kwon, 2021. "Effect of Public Empathy with Infection-Control Guidelines on Infection-Prevention Attitudes and Behaviors: Based on the Case of COVID-19," IJERPH, MDPI, vol. 18(24), pages 1-18, December.
    8. Jaeyong Lee & Calem Kenward & Liam J. Worrall & Marija Vuckovic & Francesco Gentile & Anh-Tien Ton & Myles Ng & Artem Cherkasov & Natalie C. J. Strynadka & Mark Paetzel, 2022. "X-ray crystallographic characterization of the SARS-CoV-2 main protease polyprotein cleavage sites essential for viral processing and maturation," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Maria de Lourdes Aguiar-Oliveira & Aline Campos & Aline R. Matos & Caroline Rigotto & Adriana Sotero-Martins & Paulo F. P. Teixeira & Marilda M. Siqueira, 2020. "Wastewater-Based Epidemiology (WBE) and Viral Detection in Polluted Surface Water: A Valuable Tool for COVID-19 Surveillance—A Brief Review," IJERPH, MDPI, vol. 17(24), pages 1-19, December.
    10. Yongin Choi & James Slghee Kim & Heejin Choi & Hyojung Lee & Chang Hyeong Lee, 2020. "Assessment of Social Distancing for Controlling COVID-19 in Korea: An Age-Structured Modeling Approach," IJERPH, MDPI, vol. 17(20), pages 1-16, October.
    11. Bruno Palialol & Paula Pereda & Carlos Azzoni, 2020. "Does weather influence COVID‐19 transmission?," Regional Science Policy & Practice, Wiley Blackwell, vol. 12(6), pages 981-1004, December.
    12. Fabian Zech & Daniel Schniertshauer & Christoph Jung & Alexandra Herrmann & Arne Cordsmeier & Qinya Xie & Rayhane Nchioua & Caterina Prelli Bozzo & Meta Volcic & Lennart Koepke & Janis A. Müller & Jan, 2021. "Spike residue 403 affects binding of coronavirus spikes to human ACE2," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    13. Zexun Chen & Sean Kelty & Alexandre G. Evsukoff & Brooke Foucault Welles & James Bagrow & Ronaldo Menezes & Gourab Ghoshal, 2022. "Contrasting social and non-social sources of predictability in human mobility," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    14. Muhammad Azher Hassan & Tariq Mehmood & Ehtisham Lodhi & Muhammad Bilal & Afzal Ahmed Dar & Junjie Liu, 2022. "Lockdown Amid COVID-19 Ascendancy over Ambient Particulate Matter Pollution Anomaly," IJERPH, MDPI, vol. 19(20), pages 1-31, October.
    15. Hubert Dobrowolski & Dariusz Włodarek, 2021. "Body Mass, Physical Activity and Eating Habits Changes during the First COVID-19 Pandemic Lockdown in Poland," IJERPH, MDPI, vol. 18(11), pages 1-9, May.
    16. Frederick Ahen, 2022. "Community-Level Health Interventions are Crucial in the Post-COVID-19 Era: Lessons from Africa’s Proactive Public Health Policy Interventions," Humanistic Management Journal, Springer, vol. 7(3), pages 369-390, December.
    17. Muhammad Moazzam & Muhammad Imran Sajid & Hamza Shahid & Jahanzaib Butt & Irfan Bashir & Muhammad Jamshaid & Amir Nasrolahi Shirazi & Rakesh Kumar Tiwari, 2020. "Understanding COVID-19: From Origin to Potential Therapeutics," IJERPH, MDPI, vol. 17(16), pages 1-22, August.
    18. Lei Peng & Yingxia Hu & Madeleine C. Mankowski & Ping Ren & Rita E. Chen & Jin Wei & Min Zhao & Tongqing Li & Therese Tripler & Lupeng Ye & Ryan D. Chow & Zhenhao Fang & Chunxiang Wu & Matthew B. Dong, 2022. "Monospecific and bispecific monoclonal SARS-CoV-2 neutralizing antibodies that maintain potency against B.1.617," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    19. Tasos Stylianou & Konstantinos Ntelas, 2023. "Impact of COVID-19 Pandemic on Mental Health and Socioeconomic Aspects in Greece," IJERPH, MDPI, vol. 20(3), pages 1-21, January.
    20. Jerzy Sienko & Izabela Marczak & Maciej Kotowski & Anna Bogacz & Karol Tejchman & Magdalena Sienko & Katarzyna Kotfis, 2022. "Association of ACE2 Gene Variants with the Severity of COVID-19 Disease—A Prospective Observational Study," IJERPH, MDPI, vol. 19(19), pages 1-8, October.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37786-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.