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, Ashraf Brik

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Article number6174
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - 1 Dec 2022
Externally publishedYes

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology

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