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

Ganga B. Vamisetti, Abhishek Saha, Yichao J. Huang, Rajeshwer Vanjari, Guy Mann, Julia Gutbrod, Nabieh Ayoub, Hiroaki Suga () and Ashraf Brik ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33808-6

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