IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-27072-3.html
   My bibliography  Save this article

Design of modular autoproteolytic gene switches responsive to anti-coronavirus drug candidates

Author

Listed:
  • Nik Franko

    (ETH Zurich, Department of Biosystems Science and Engineering)

  • Ana Palma Teixeira

    (ETH Zurich, Department of Biosystems Science and Engineering)

  • Shuai Xue

    (ETH Zurich, Department of Biosystems Science and Engineering)

  • Ghislaine Charpin-El Hamri

    (Institut Universitaire de Technologie)

  • Martin Fussenegger

    (ETH Zurich, Department of Biosystems Science and Engineering
    University of Basel, Faculty of Life Science)

Abstract

The main (Mpro) and papain-like (PLpro) proteases encoded by SARS-CoV-2 are essential to process viral polyproteins into functional units, thus representing key targets for anti-viral drug development. There is a need for an efficient inhibitor screening system that can identify drug candidates in a cellular context. Here we describe modular, tunable autoproteolytic gene switches (TAGS) relying on synthetic transcription factors that self-inactivate, unless in the presence of coronavirus protease inhibitors, consequently activating transgene expression. TAGS rapidly report the impact of drug candidates on Mpro and PLpro activities with a high signal-to-noise response and a sensitivity matching concentration ranges inhibiting viral replication. The modularity of the TAGS enabled the study of other Coronaviridae proteases, characterization of mutations and multiplexing of gene switches in human cells. Mice implanted with Mpro or PLpro TAGS-engineered cells enabled analysis of the activity and bioavailability of protease inhibitors in vivo in a virus-free setting.

Suggested Citation

  • Nik Franko & Ana Palma Teixeira & Shuai Xue & Ghislaine Charpin-El Hamri & Martin Fussenegger, 2021. "Design of modular autoproteolytic gene switches responsive to anti-coronavirus drug candidates," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27072-3
    DOI: 10.1038/s41467-021-27072-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-27072-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-27072-3?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. Velia Siciliano & Breanna DiAndreth & Blandine Monel & Jacob Beal & Jin Huh & Kiera L Clayton & Liliana Wroblewska & AnneMarie McKeon & Bruce D. Walker & Ron Weiss, 2018. "Engineering modular intracellular protein sensor-actuator devices," Nature Communications, Nature, vol. 9(1), pages 1-7, December.
    2. Donghyuk Shin & Rukmini Mukherjee & Diana Grewe & Denisa Bojkova & Kheewoong Baek & Anshu Bhattacharya & Laura Schulz & Marek Widera & Ahmad Reza Mehdipour & Georg Tascher & Paul P. Geurink & Alexande, 2020. "Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity," Nature, Nature, vol. 587(7835), pages 657-662, November.
    3. Zhenming Jin & Xiaoyu Du & Yechun Xu & Yongqiang Deng & Meiqin Liu & Yao Zhao & Bing Zhang & Xiaofeng Li & Leike Zhang & Chao Peng & Yinkai Duan & Jing Yu & Lin Wang & Kailin Yang & Fengjiang Liu & Re, 2020. "Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors," Nature, Nature, vol. 582(7811), pages 289-293, June.
    4. Federica Cella & Liliana Wroblewska & Ron Weiss & Velia Siciliano, 2018. "Engineering protein-protein devices for multilayered regulation of mRNA translation using orthogonal proteases in mammalian cells," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    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. Shunsuke Kawasaki & Hiroki Ono & Moe Hirosawa & Takeru Kuwabara & Shunsuke Sumi & Suji Lee & Knut Woltjen & Hirohide Saito, 2023. "Programmable mammalian translational modulators by CRISPR-associated proteins," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Rana Abdelnabi & Dirk Jochmans & Kim Donckers & Bettina Trüeb & Nadine Ebert & Birgit Weynand & Volker Thiel & Johan Neyts, 2023. "Nirmatrelvir-resistant SARS-CoV-2 is efficiently transmitted in female Syrian hamsters and retains partial susceptibility to treatment," Nature Communications, Nature, vol. 14(1), pages 1-7, December.
    3. 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.
    4. Jolien Van Cleemput & Willem van Snippenberg & Laurens Lambrechts & Amélie Dendooven & Valentino D’Onofrio & Liesbeth Couck & Wim Trypsteen & Jan Vanrusselt & Sebastiaan Theuns & Nick Vereecke & Thier, 2021. "Organ-specific genome diversity of replication-competent SARS-CoV-2," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    5. Mohammad Afsar & GuanQun Liu & Lijia Jia & Eliza A. Ruben & Digant Nayak & Zuberwasim Sayyad & Priscila dos Santos Bury & Kristin E. Cano & Anindita Nayak & Xiang Ru Zhao & Ankita Shukla & Patrick Sun, 2023. "Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. 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.
    7. Mohammad (Behdad) Jamshidi & Omid Moztarzadeh & Alireza Jamshidi & Ahmed Abdelgawad & Ayman S. El-Baz & Lukas Hauer, 2023. "Future of Drug Discovery: The Synergy of Edge Computing, Internet of Medical Things, and Deep Learning," Future Internet, MDPI, vol. 15(4), pages 1-15, April.
    8. Lisa-Marie Funk & Gereon Poschmann & Fabian Rabe von Pappenheim & Ashwin Chari & Kim M. Stegmann & Antje Dickmanns & Marie Wensien & Nora Eulig & Elham Paknia & Gabi Heyne & Elke Penka & Arwen R. Pear, 2024. "Multiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    9. Ala M. Shaqra & Sarah N. Zvornicanin & Qiu Yu J. Huang & Gordon J. Lockbaum & Mark Knapp & Laura Tandeske & David T. Bakan & Julia Flynn & Daniel N. A. Bolon & Stephanie Moquin & Dustin Dovala & Nese , 2022. "Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Sara Sunshine & Andreas S. Puschnik & Joseph M. Replogle & Matthew T. Laurie & Jamin Liu & Beth Shoshana Zha & James K. Nuñez & Janie R. Byrum & Aidan H. McMorrow & Matthew B. Frieman & Juliane Winkle, 2023. "Systematic functional interrogation of SARS-CoV-2 host factors using Perturb-seq," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    11. Yida Jiang & Xinghe Zhang & Honggang Nie & Jianxiong Fan & Shuangshuang Di & Hui Fu & Xiu Zhang & Lijuan Wang & Chun Tang, 2024. "Dissecting diazirine photo-reaction mechanism for protein residue-specific cross-linking and distance mapping," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    12. Shodai Komatsu & Hirohisa Ohno & Hirohide Saito, 2023. "Target-dependent RNA polymerase as universal platform for gene expression control in response to intracellular molecules," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    13. Pawel M. Wydorski & Jerzy Osipiuk & Benjamin T. Lanham & Christine Tesar & Michael Endres & Elizabeth Engle & Robert Jedrzejczak & Vishruth Mullapudi & Karolina Michalska & Krzysztof Fidelis & David F, 2023. "Dual domain recognition determines SARS-CoV-2 PLpro selectivity for human ISG15 and K48-linked di-ubiquitin," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    14. Zeyin Yan & Dacong Wei & Xin Li & Lung Wa Chung, 2024. "Accelerating reliable multiscale quantum refinement of protein–drug systems enabled by machine learning," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    15. Xinyu Wu & Margareta Go & Julie V. Nguyen & Nathan W. Kuchel & Bernadine G. C. Lu & Kathleen Zeglinski & Kym N. Lowes & Dale J. Calleja & Jeffrey P. Mitchell & Guillaume Lessene & David Komander & Mat, 2024. "Mutational profiling of SARS-CoV-2 papain-like protease reveals requirements for function, structure, and drug escape," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    16. Michael H. J. Rhodin & Archie C. Reyes & Anand Balakrishnan & Nalini Bisht & Nicole M. Kelly & Joyce Sweeney Gibbons & Jonathan Lloyd & Michael Vaine & Tessa Cressey & Miranda Crepeau & Ruichao Shen &, 2024. "The small molecule inhibitor of SARS-CoV-2 3CLpro EDP-235 prevents viral replication and transmission in vivo," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    17. Yage Ding & Cristina Tous & Jaehoon Choi & Jingyao Chen & Wilson W. Wong, 2024. "Orthogonal inducible control of Cas13 circuits enables programmable RNA regulation in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    18. Iona Wallace & Kheewoong Baek & J. Rajan Prabu & Ronnald Vollrath & Susanne Gronau & Brenda A. Schulman & Kirby N. Swatek, 2023. "Insights into the ISG15 transfer cascade by the UBE1L activating enzyme," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    19. Xiangrui Jiang & Haixia Su & Weijuan Shang & Feng Zhou & Yan Zhang & Wenfeng Zhao & Qiumeng Zhang & Hang Xie & Lei Jiang & Tianqing Nie & Feipu Yang & Muya Xiong & Xiaoxing Huang & Minjun Li & Ping Ch, 2023. "Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    20. Ella Borberg & Eran Granot & Fernando Patolsky, 2022. "Ultrafast one-minute electronic detection of SARS-CoV-2 infection by 3CLpro enzymatic activity in untreated saliva samples," Nature Communications, Nature, vol. 13(1), pages 1-11, 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:12:y:2021:i:1:d:10.1038_s41467-021-27072-3. 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.