In vivo modulation of ubiquitin chains by N -methylated non-proteinogenic cyclic peptides

Joseph M. Rogers, Mickal Nawatha, Betsegaw Lemma, Ganga B. Vamisetti, Ido Livneh, Uri Barash, Israel Vlodavsky, Aaron Ciechanover, David Fushman, Hiroaki Suga, Ashraf Brik

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Cancer and other disease states can change the landscape of proteins post-translationally tagged with ubiquitin (Ub) chains. Molecules capable of modulating the functions of Ub chains are potential therapeutic agents, but their discovery represents a significant challenge. Recently, it was shown that de novo cyclic peptides, selected from trillion-member random libraries, are capable of binding particular Ub chains. However, these peptides were overwhelmingly proteinogenic, so the prospect of in vivo activity was uncertain. Here, we report the discovery of small, non-proteinogenic cyclic peptides, rich in non-canonical features like N-methylation, which can tightly bind Lys48-linked Ub chains. These peptides engage three Lys48-linked Ub units simultaneously, block the action of deubiquitinases and the proteasome, induce apoptosis in vitro, and attenuate tumor growth in vivo. This highlights the potential of non-proteinogenic cyclic peptide screening to rapidly find in vivo-active leads, and the targeting of ubiquitin chains as a promising anti-cancer mechanism of action.

Original languageEnglish
Pages (from-to)513-522
Number of pages10
JournalRSC Chemical Biology
Issue number2
StatePublished - 1 Apr 2021
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Biochemistry
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)


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