Conformationally Constrained Peptidomimetics as Inhibitors of the Protein Arginine Methyl Transferases
Research output: Contribution to journal › Journal article › Research › peer-review
Astrid Knuhtsen, Baptiste Legrand, Olivier Van der Poorten, Muriel Amblard, Jean Martinez, Steven Ballet, Jesper L Kristensen, Daniel Sejer Pedersen
Protein arginine N-methyl transferases (PRMTs) belong to a family of enzymes that modulate the epigenetic code through modifications of histones. In the present study, peptides emerging from a phage display screening were modified in the search for PRMT inhibitors through substitution with non-proteinogenic amino acids, N-alkylation of the peptide backbone, and incorporation of constrained dipeptide mimics. One of the modified peptides (23) showed an increased inhibitory activity towards several PRMTs in the low μm range and the conformational preference of this peptide was investigated and compared with the original hit using circular dichroism and NMR spectroscopy. Introducing two constrained tryptophan residue mimics (l-Aia) spaced by a single amino acid was found to induce a unique turn structure stabilized by a hydrogen bond and aromatic π-stacking interaction between the two l-Aia residues.
|Journal||Chemistry: A European Journal|
|Number of pages||7|
|Publication status||Published - 12 Aug 2016|