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Updated: Oct 31, 2025
In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
Published on: July 25, 2019
In vivo modulation of ubiquitin chains by N-methylated non-proteinogenic cyclic peptides
Joseph M Rogers1,2, Mickal Nawatha3, Betsegaw Lemma4
1Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Abstract:
Cancer and other disease states can change the landscape of proteins post-translationally tagged with ubiquitin (Ub) chains. Molecules capable of modulating 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 and specifically 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.
Insights
Researchers discovered non-proteinogenic cyclic peptides that target ubiquitin chains. These molecules show promise as anti-cancer therapeutics by blocking key cellular processes and reducing tumor growth in vivo.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer alters protein ubiquitination, creating therapeutic targets.
- Modulating ubiquitin (Ub) chains is a potential anti-cancer strategy.
- Previous cyclic peptides targeting Ub chains were mostly proteinogenic, limiting in vivo potential.
Purpose of the Study:
- To discover non-proteinogenic cyclic peptides that specifically bind Lys48-linked ubiquitin chains.
- To evaluate the therapeutic potential of these novel peptides against cancer.
Main Methods:
- Screening of trillion-member random libraries for de novo cyclic peptides.
- Characterization of peptide binding to Lys48-linked Ub chains.
- Assessing peptide effects on deubiquitinases, proteasome activity, apoptosis, and tumor growth in vitro and in vivo.
Main Results:
- Identified small, non-proteinogenic cyclic peptides with non-canonical features (e.g., N-methylation).
- These peptides bind Lys48-linked Ub chains, engaging up to three Ub units.
- Peptides inhibit deubiquitinases and proteasome function, induce apoptosis, and reduce tumor growth in vivo.
Conclusions:
- Non-proteinogenic cyclic peptide screening is effective for identifying in vivo-active therapeutic leads.
- Targeting ubiquitin chains represents a viable anti-cancer mechanism of action.
- These novel peptides offer a promising new avenue for cancer therapy.
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