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Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair

Author

Listed:
  • Ganga B. Vamisetti

    (Technion-Israel Institute of Technology)

  • Abhishek Saha

    (Technion-Israel Institute of Technology)

  • Yichao J. Huang

    (The University of Tokyo)

  • Rajeshwer Vanjari

    (Technion-Israel Institute of Technology)

  • Guy Mann

    (Technion-Israel Institute of Technology)

  • Julia Gutbrod

    (Technion-Israel Institute of Technology)

  • Nabieh Ayoub

    (Technion-Israel Institute of Technology, Haifa)

  • Hiroaki Suga

    (The University of Tokyo)

  • Ashraf Brik

    (Technion-Israel Institute of Technology)

Abstract

Developing an effective binder for a specific ubiquitin (Ub) chain is a promising approach for modulating various biological processes with potential applications in drug discovery. Here, we combine the Random Non-standard Peptides Integrated Discovery (RaPID) method and chemical protein synthesis to screen an extended library of macrocyclic peptides against synthetic Lys63-linked Di-Ub to discover a specific binder for this Ub chain. Furthermore, next-generation binders are generated by chemical modifications. We show that our potent cyclic peptide is cell-permeable, and inhibits DNA damage repair, leading to apoptotic cell death. Concordantly, a pulldown experiment with the biotinylated analog of our lead cyclic peptide supports our findings. Collectively, we establish a powerful strategy for selective inhibition of protein-protein interactions associated with Lys63-linked Di-Ub using cyclic peptides. This study offers an advancement in modulating central Ub pathways and provides opportunities in drug discovery areas associated with Ub signaling.

Suggested Citation

  • Ganga B. Vamisetti & Abhishek Saha & Yichao J. Huang & Rajeshwer Vanjari & Guy Mann & Julia Gutbrod & Nabieh Ayoub & Hiroaki Suga & Ashraf Brik, 2022. "Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33808-6
    DOI: 10.1038/s41467-022-33808-6
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    References listed on IDEAS

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    1. Hikaru Tsuchiya & Daocharad Burana & Fumiaki Ohtake & Naoko Arai & Ai Kaiho & Masayuki Komada & Keiji Tanaka & Yasushi Saeki, 2018. "Ub-ProT reveals global length and composition of protein ubiquitylation in cells," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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    Cited by:

    1. Betsegaw Lemma & Di Zhang & Ganga B. Vamisetti & Bryan G. Wentz & Hiroaki Suga & Ashraf Brik & Jacek Lubkowski & David Fushman, 2023. "Mechanism of selective recognition of Lys48-linked polyubiquitin by macrocyclic peptide inhibitors of proteasomal degradation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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