title: Conformationally Constrained Peptidomimetics as Inhibitors of the Protein Arginine Methyl Transferases.
abstract: 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.
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors: Astrid
authors: A
authors: Knuhtsen
authors: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, 15 Avenue Charles Flahault, 34093, Montpellier, cedex 5, France.
authors: Baptiste
authors: B
authors: Legrand
authors: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
authors: Olivier
authors: O
authors: Van der Poorten
authors: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, 15 Avenue Charles Flahault, 34093, Montpellier, cedex 5, France.
authors: Muriel
authors: M
authors: Amblard
authors: Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS-Université Montpellier-ENSCM, 15 Avenue Charles Flahault, 34093, Montpellier, cedex 5, France.
authors: Jean
authors: J
authors: Martinez
authors: Research Group of Organic Chemistry, Departments of Chemistry and Bio-engineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussels, Belgium.
authors: Steven
authors: S
authors: Ballet
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors: Jesper L
authors: JL
authors: Kristensen
authors: Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark. daniel.pedersen@sund.ku.dk.
authors: Daniel Sejer
authors: http://orcid.org/0000-0003-3926-7047
authors: DS
authors: Pedersen
mesh_terms: D000478:Alkylation; D000595:Amino Acid Sequence; D061505:Cell Surface Display Techniques; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D057786:Peptidomimetics; D011484:Protein-Arginine N-Methyltransferases
keywords: NMR; PRMT inhibitor; azepinone; epigenetics; peptidomimetics