Issue 2, 2021

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

Abstract

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.

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

Associated articles

Supplementary files

Transparent peer review

To support increased transparency, we offer authors the option to publish the peer review history alongside their article.

View this article’s peer review history

Article information

Article type
Paper
Submitted
03 Oct 2020
Accepted
30 Nov 2020
First published
16 Dec 2020
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2021,2, 513-522

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

J. M. Rogers, M. Nawatha, B. Lemma, G. B. Vamisetti, I. Livneh, U. Barash, I. Vlodavsky, A. Ciechanover, D. Fushman, H. Suga and A. Brik, RSC Chem. Biol., 2021, 2, 513 DOI: 10.1039/D0CB00179A

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements