In vivo modulation of ubiquitin chains by N -methylated non-proteinogenic cyclic peptides
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In vivo modulation of ubiquitin chains by N -methylated non-proteinogenic cyclic peptides. / Rogers, Joseph M.; Nawatha, Mickal; Lemma, Betsegaw; Vamisetti, Ganga B.; Livneh, Ido; Barash, Uri; Vlodavsky, Israel; Ciechanover, Aaron; Fushman, David; Suga, Hiroaki; Brik, Ashraf.
In: RSC Chemical Biology, Vol. 2, No. 2, 2021, p. 513-522.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - In vivo modulation of ubiquitin chains by N -methylated non-proteinogenic cyclic peptides
AU - Rogers, Joseph M.
AU - Nawatha, Mickal
AU - Lemma, Betsegaw
AU - Vamisetti, Ganga B.
AU - Livneh, Ido
AU - Barash, Uri
AU - Vlodavsky, Israel
AU - Ciechanover, Aaron
AU - Fushman, David
AU - Suga, Hiroaki
AU - Brik, Ashraf
N1 - Correction: In vivo modulation of ubiquitin chains by N-methylated non-proteinogenic cyclic peptides (RSC Chem. Biol. (2021) 2 (513-522) DOI: 10.1039/D0CB00179A
PY - 2021
Y1 - 2021
N2 - Cyclic peptides containing unnatural amino acids can modulate Lys-48 ubiquitin chains in cells and animals. 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.
AB - Cyclic peptides containing unnatural amino acids can modulate Lys-48 ubiquitin chains in cells and animals. 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.
U2 - 10.1039/d0cb00179a
DO - 10.1039/d0cb00179a
M3 - Journal article
C2 - 34179781
VL - 2
SP - 513
EP - 522
JO - RSC Chemical Biology
JF - RSC Chemical Biology
SN - 2633-0679
IS - 2
ER -
ID: 260400799