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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
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    1. 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.
    2. 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.
    3. 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.
    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.
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