Conformationally Constrained Peptidomimetics as Inhibitors of the Protein Arginine Methyl Transferases

Astrid Knuhtsen; Baptiste Legrand; Olivier Van der Poorten; Muriel Amblard; Jean Martinez; Steven Ballet; Jesper L Kristensen; Daniel Sejer Pedersen

doi:10.1002/chem.201602518

Conformationally Constrained Peptidomimetics as Inhibitors of the Protein Arginine Methyl Transferases

Astrid Knuhtsen, Baptiste Legrand, Olivier Van der Poorten, Muriel Amblard, Jean Martinez, Steven Ballet, Jesper L Kristensen, Daniel Sejer Pedersen

5 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Chemistry: A European Journal
Vol/bind	22
Udgave nummer	39
Sider (fra-til)	14022–14028
Antal sider	7
ISSN	0947-6539
DOI	https://doi.org/10.1002/chem.201602518
Status	Udgivet - 19 sep. 2016

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10.1002/chem.201602518

Citationsformater

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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.",

author = "Astrid Knuhtsen and Baptiste Legrand and {Van der Poorten}, Olivier and Muriel Amblard and Jean Martinez and Steven Ballet and Kristensen, {Jesper L} and Pedersen, {Daniel Sejer}",

note = "{\textcopyright} 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",

year = "2016",

month = sep,

day = "19",

doi = "10.1002/chem.201602518",

language = "English",

volume = "22",

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TY - JOUR

T1 - Conformationally Constrained Peptidomimetics as Inhibitors of the Protein Arginine Methyl Transferases

AU - Knuhtsen, Astrid

AU - Legrand, Baptiste

AU - Van der Poorten, Olivier

AU - Amblard, Muriel

AU - Martinez, Jean

AU - Ballet, Steven

AU - Kristensen, Jesper L

AU - Pedersen, Daniel Sejer

PY - 2016/9/19

Y1 - 2016/9/19

N2 - 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.

AB - 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.

U2 - 10.1002/chem.201602518

DO - 10.1002/chem.201602518

M3 - Journal article

C2 - 27515561

SN - 0947-6539

VL - 22

SP - 14022

EP - 14028

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

IS - 39

ER -

Conformationally Constrained Peptidomimetics as Inhibitors of the Protein Arginine Methyl Transferases

Abstract

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