Bioconjugate Platform for Iterative Backbone N-Methylation of Peptides.
ACS Catal
; 12(22): 14006-14014, 2022 Nov 18.
Article
em En
| MEDLINE
| ID: mdl-36793448
ABSTRACT
N-methylation of peptide backbones has often been utilized as a strategy towards the development of peptidic drugs. However, difficulties in the chemical synthesis, high cost of enantiopure N-methyl building blocks, and subsequent coupling inefficiencies have hampered larger-scale medicinal chemical efforts. Here, we present a chemoenzymatic strategy for backbone N-methylation by bioconjugation of peptides of interest to the catalytic scaffold of a borosin-type methyltransferase. Crystal structures of a substrate tolerant enzyme from Mycena rosella guided the design of a decoupled catalytic scaffold that can be linked via a heterobifunctional crosslinker to any peptide substrate of choice. Peptides linked to the scaffold, including those with non-proteinogenic residues, show robust backbone N-methylation. Various crosslinking strategies were tested to facilitate substrate disassembly, which enabled a reversible bioconjugation approach that efficiently released modified peptide. Our results provide general framework for the backbone N-methylation on any peptide of interest and may facilitate the production of large libraries of N-methylated peptides.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
ACS Catal
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos