期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 4, 页码 1813-1820出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202009749
关键词
cyclization; inhibitors; peptides; protein– protein interactions; structure-based design
资金
- Alexander von Humboldt foundation
- Max Planck Society
- Aventis Foundation
- Stiftung Stipendien-Fonds of the Verbandes der Chemischen Industrie (VCI)
- Projekt DEAL
Researchers have developed peptide inhibitors targeting RbAp48 protein, successfully inhibiting the interaction between RbAp48 and MTA1 with high stability. Through a structure-based design strategy, the goal of improving affinity was achieved.
The scaffolding protein RbAp48 is part of several epigenetic regulation complexes and is overexpressed in a variety of cancers. In order to develop tool compounds for the study of RbAp48 function, we have developed peptide inhibitors targeting the protein-protein interaction interface between RbAp48 and the scaffold protein MTA1. Based on a MTA1-derived linear peptide with low micromolar affinity and informed by crystallographic analysis, a bicyclic peptide was developed that inhibits the RbAp48/MTA1 interaction with a very low nanomolar K-D value of 8.56 nM, and which showed appreciable stability against cellular proteases. Design included exchange of a polar amide cyclization strategy to hydrophobic aromatic linkers enabling mono- and bicyclization by means of cysteine alkylation, which improved affinity by direct interaction of the linkers with a hydrophobic residue on RbAp48. Our results demonstrate that stepwise evolution of a structure-based design is a suitable strategy for inhibitor development targeting PPIs.
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