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Chemical evolution of an autonomous DNAzyme with allele-specific gene silencing activity

Author

Listed:
  • Kim Nguyen

    (University of California)

  • Turnee N. Malik

    (University of California)

  • John C. Chaput

    (University of California
    University of California
    University of California
    University of California)

Abstract

Low activity has been the primary obstacle impeding the use of DNA enzymes (DNAzymes) as gene silencing agents in clinical applications. Here we describe the chemical evolution of a DNAzyme with strong catalytic activity under near physiological conditions. The enzyme achieves ~65 turnovers in 30 minutes, a feat only previously witnessed by the unmodified parent sequence under forcing conditions of elevated Mg2+ and pH. Structural constraints imposed by the chemical modifications drive catalysis toward a highly preferred UGUD motif (cut site underlined) that was validated by positive and negative predictions. Biochemical assays support an autonomous RNA cleavage mechanism independent of RNase H1 engagement. Consistent with its strong catalytic activity, the enzyme exhibits persistent allele-specific knock-down of an endogenous mRNA encoding an undruggable oncogenic KRAS target. Together, these results demonstrate that chemical evolution offers a powerful approach for discovering new chemotype combinations that can imbue DNAzymes with the physicochemical properties necessary to support therapeutic applications.

Suggested Citation

  • Kim Nguyen & Turnee N. Malik & John C. Chaput, 2023. "Chemical evolution of an autonomous DNAzyme with allele-specific gene silencing activity," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38100-9
    DOI: 10.1038/s41467-023-38100-9
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    1. Jude Canon & Karen Rex & Anne Y. Saiki & Christopher Mohr & Keegan Cooke & Dhanashri Bagal & Kevin Gaida & Tyler Holt & Charles G. Knutson & Neelima Koppada & Brian A. Lanman & Jonathan Werner & Aaron, 2019. "The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity," Nature, Nature, vol. 575(7781), pages 217-223, November.
    2. Yajun Wang & Arlene K. Ngor & Ali Nikoomanzar & John C. Chaput, 2018. "Evolution of a General RNA-Cleaving FANA Enzyme," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    3. Jan Borggräfe & Julian Victor & Hannah Rosenbach & Aldino Viegas & Christoph G. W. Gertzen & Christine Wuebben & Helena Kovacs & Mohanraj Gopalswamy & Detlev Riesner & Gerhard Steger & Olav Schiemann , 2022. "Time-resolved structural analysis of an RNA-cleaving DNA catalyst," Nature, Nature, vol. 601(7891), pages 144-149, January.
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