IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-39158-1.html
   My bibliography  Save this article

Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2

Author

Listed:
  • Katherine U. Gaynor

    (Portway Building, Granta Park)

  • Marina Vaysburd

    (Francis Crick Avenue)

  • Maximilian A. J. Harman

    (Portway Building, Granta Park)

  • Anna Albecka

    (Francis Crick Avenue)

  • Phillip Jeffrey

    (Portway Building, Granta Park)

  • Paul Beswick

    (Portway Building, Granta Park)

  • Guido Papa

    (Francis Crick Avenue)

  • Liuhong Chen

    (Portway Building, Granta Park)

  • Donna Mallery

    (Francis Crick Avenue)

  • Brian McGuinness

    (Portway Building, Granta Park)

  • Katerine Rietschoten

    (Portway Building, Granta Park)

  • Steven Stanway

    (Portway Building, Granta Park)

  • Paul Brear

    (University of Cambridge)

  • Aleksei Lulla

    (University of Cambridge)

  • Katarzyna Ciazynska

    (Francis Crick Avenue)

  • Veronica T. Chang

    (Francis Crick Avenue)

  • Jo Sharp

    (University of Liverpool)

  • Megan Neary

    (University of Liverpool)

  • Helen Box

    (University of Liverpool)

  • Jo Herriott

    (University of Liverpool)

  • Edyta Kijak

    (University of Liverpool)

  • Lee Tatham

    (University of Liverpool)

  • Eleanor G. Bentley

    (University of Liverpool)

  • Parul Sharma

    (University of Liverpool)

  • Adam Kirby

    (University of Liverpool)

  • Ximeng Han

    (University of Liverpool)

  • James P. Stewart

    (University of Liverpool)

  • Andrew Owen

    (University of Liverpool)

  • John A. G. Briggs

    (Francis Crick Avenue
    Max Planck Institute of Biochemistry)

  • Marko Hyvönen

    (University of Cambridge)

  • Michael J. Skynner

    (Portway Building, Granta Park)

  • Leo C. James

    (Francis Crick Avenue)

Abstract

COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles’ inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

Suggested Citation

  • Katherine U. Gaynor & Marina Vaysburd & Maximilian A. J. Harman & Anna Albecka & Phillip Jeffrey & Paul Beswick & Guido Papa & Liuhong Chen & Donna Mallery & Brian McGuinness & Katerine Rietschoten & , 2023. "Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39158-1
    DOI: 10.1038/s41467-023-39158-1
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-39158-1
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-39158-1?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. 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.
    2. Pengfei Wang & Manoj S. Nair & Lihong Liu & Sho Iketani & Yang Luo & Yicheng Guo & Maple Wang & Jian Yu & Baoshan Zhang & Peter D. Kwong & Barney S. Graham & John R. Mascola & Jennifer Y. Chang & Mich, 2021. "Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7," Nature, Nature, vol. 593(7857), pages 130-135, May.
    3. Donald J. Benton & Antoni G. Wrobel & Pengqi Xu & Chloë Roustan & Stephen R. Martin & Peter B. Rosenthal & John J. Skehel & Steven J. Gamblin, 2020. "Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion," Nature, Nature, vol. 588(7837), pages 327-330, December.
    4. 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.
    5. Qian Wang & Yicheng Guo & Sho Iketani & Manoj S. Nair & Zhiteng Li & Hiroshi Mohri & Maple Wang & Jian Yu & Anthony D. Bowen & Jennifer Y. Chang & Jayesh G. Shah & Nadia Nguyen & Zhiwei Chen & Kathrin, 2022. "Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5," Nature, Nature, vol. 608(7923), pages 603-608, August.
    6. Delphine Planas & Nell Saunders & Piet Maes & Florence Guivel-Benhassine & Cyril Planchais & Julian Buchrieser & William-Henry Bolland & Françoise Porrot & Isabelle Staropoli & Frederic Lemoine & Hélè, 2022. "Considerable escape of SARS-CoV-2 Omicron to antibody neutralization," Nature, Nature, vol. 602(7898), pages 671-675, February.
    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. Guoli Shi & Tiansheng Li & Kin Kui Lai & Reed F. Johnson & Jonathan W. Yewdell & Alex A. Compton, 2024. "Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Xuanming Guo & Jianli Cao & Jian-Piao Cai & Jiayan Wu & Jiangang Huang & Pallavi Asthana & Sheung Kin Ken Wong & Zi-Wei Ye & Susma Gurung & Yijing Zhang & Sheng Wang & Zening Wang & Xin Ge & Hiu Yee K, 2022. "Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Nikhil Kumar Tulsian & Raghuvamsi Venkata Palur & Xinlei Qian & Yue Gu & Bhuvaneshwari D/O Shunmuganathan & Firdaus Samsudin & Yee Hwa Wong & Jianqing Lin & Kiren Purushotorman & Mary McQueen Kozma & , 2023. "Defining neutralization and allostery by antibodies against COVID-19 variants," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    4. Yin-Feng Kang & Cong Sun & Jing Sun & Chu Xie & Zhen Zhuang & Hui-Qin Xu & Zheng Liu & Yi-Hao Liu & Sui Peng & Run-Yu Yuan & Jin-Cun Zhao & Mu-Sheng Zeng, 2022. "Quadrivalent mosaic HexaPro-bearing nanoparticle vaccine protects against infection of SARS-CoV-2 variants," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Sapna Sharma & Thomas Vercruysse & Lorena Sanchez-Felipe & Winnie Kerstens & Madina Rasulova & Lindsey Bervoets & Carolien Keyzer & Rana Abdelnabi & Caroline S. Foo & Viktor Lemmens & Dominique Loover, 2022. "Updated vaccine protects against SARS-CoV-2 variants including Omicron (B.1.1.529) and prevents transmission in hamsters," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    6. Zhennan Zhao & Yufeng Xie & Bin Bai & Chunliang Luo & Jingya Zhou & Weiwei Li & Yumin Meng & Linjie Li & Dedong Li & Xiaomei Li & Xiaoxiong Li & Xiaoyun Wang & Junqing Sun & Zepeng Xu & Yeping Sun & W, 2023. "Structural basis for receptor binding and broader interspecies receptor recognition of currently circulating Omicron sub-variants," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Denis Mongin & Nils Bürgisser & Gustavo Laurie & Guillaume Schimmel & Diem-Lan Vu & Stephane Cullati & Delphine Sophie Courvoisier, 2023. "Effect of SARS-CoV-2 prior infection and mRNA vaccination on contagiousness and susceptibility to infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    8. 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.
    9. 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.
    10. Tingting Li & Xiaojian Han & Chenjian Gu & Hangtian Guo & Huajun Zhang & Yingming Wang & Chao Hu & Kai Wang & Fengjiang Liu & Feiyang Luo & Yanan Zhang & Jie Hu & Wang Wang & Shenglong Li & Yanan Hao , 2021. "Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    11. Delphine Planas & Isabelle Staropoli & Vincent Michel & Frederic Lemoine & Flora Donati & Matthieu Prot & Francoise Porrot & Florence Guivel-Benhassine & Banujaa Jeyarajah & Angela Brisebarre & Océane, 2024. "Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    12. 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.
    13. Zhennan Zhao & Jingya Zhou & Mingxiong Tian & Min Huang & Sheng Liu & Yufeng Xie & Pu Han & Chongzhi Bai & Pengcheng Han & Anqi Zheng & Lutang Fu & Yuanzhu Gao & Qi Peng & Ying Li & Yan Chai & Zengyua, 2022. "Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    14. Hiam Chemaitelly & Houssein H. Ayoub & Peter Coyle & Patrick Tang & Hadi M. Yassine & Hebah A. Al-Khatib & Maria K. Smatti & Mohammad R. Hasan & Zaina Al-Kanaani & Einas Al-Kuwari & Andrew Jeremijenko, 2022. "Protection of Omicron sub-lineage infection against reinfection with another Omicron sub-lineage," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    15. Cai He & Jingyun Yang & Weiqi Hong & Zimin Chen & Dandan Peng & Hong Lei & Aqu Alu & Xuemei He & Zhenfei Bi & Xiaohua Jiang & Guowen Jia & Yun Yang & Yanan Zhou & Wenhai Yu & Cong Tang & Qing Huang & , 2022. "A self-assembled trimeric protein vaccine induces protective immunity against Omicron variant," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    16. Rong Zhu & Daniel Canena & Mateusz Sikora & Miriam Klausberger & Hannah Seferovic & Ahmad Reza Mehdipour & Lisa Hain & Elisabeth Laurent & Vanessa Monteil & Gerald Wirnsberger & Ralph Wieneke & Robert, 2022. "Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    17. Weizhong Li & Tao Wang & Arunraj M. Rajendrakumar & Gyanada Acharya & Zizhen Miao & Berin P. Varghese & Hailiang Yu & Bibek Dhakal & Tanya LeRoith & Athira Karunakaran & Wenbin Tuo & Xiaoping Zhu, 2023. "An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    18. Sun Jin Kim & Zhong Yao & Morgan C. Marsh & Debra M. Eckert & Michael S. Kay & Anna Lyakisheva & Maria Pasic & Aiyush Bansal & Chaim Birnboim & Prabhat Jha & Yannick Galipeau & Marc-André Langlois & J, 2022. "Homogeneous surrogate virus neutralization assay to rapidly assess neutralization activity of anti-SARS-CoV-2 antibodies," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    19. Saya Moriyama & Yuki Anraku & Shunta Taminishi & Yu Adachi & Daisuke Kuroda & Shunsuke Kita & Yusuke Higuchi & Yuhei Kirita & Ryutaro Kotaki & Keisuke Tonouchi & Kohei Yumoto & Tateki Suzuki & Taiyou , 2023. "Structural delineation and computational design of SARS-CoV-2-neutralizing antibodies against Omicron subvariants," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    20. Yubin Liu & Ziyi Wang & Xinyu Zhuang & Shengnan Zhang & Zhicheng Chen & Yan Zou & Jie Sheng & Tianpeng Li & Wanbo Tai & Jinfang Yu & Yanqun Wang & Zhaoyong Zhang & Yunfeng Chen & Liangqin Tong & Xi Yu, 2023. "Inactivated vaccine-elicited potent antibodies can broadly neutralize SARS-CoV-2 circulating variants," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    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_s41467-023-39158-1. 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.