Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8. / Dorosz, Jerzy; Olsen, Lars; Seger, Signe Teuber; Steinhauer, Cornelia; Bouras, Giorgos; Helgstrand, Charlotte; Wiuf, Anders; Gajhede, Michael.

In: ChemBioChem, Vol. 18, No. 14, 18.07.2017, p. 1369-1375.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Dorosz, J, Olsen, L, Seger, ST, Steinhauer, C, Bouras, G, Helgstrand, C, Wiuf, A & Gajhede, M 2017, 'Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8', ChemBioChem, vol. 18, no. 14, pp. 1369-1375. https://doi.org/10.1002/cbic.201700109

APA

Dorosz, J., Olsen, L., Seger, S. T., Steinhauer, C., Bouras, G., Helgstrand, C., ... Gajhede, M. (2017). Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8. ChemBioChem, 18(14), 1369-1375. https://doi.org/10.1002/cbic.201700109

Vancouver

Dorosz J, Olsen L, Seger ST, Steinhauer C, Bouras G, Helgstrand C et al. Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8. ChemBioChem. 2017 Jul 18;18(14):1369-1375. https://doi.org/10.1002/cbic.201700109

Author

Dorosz, Jerzy ; Olsen, Lars ; Seger, Signe Teuber ; Steinhauer, Cornelia ; Bouras, Giorgos ; Helgstrand, Charlotte ; Wiuf, Anders ; Gajhede, Michael. / Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8. In: ChemBioChem. 2017 ; Vol. 18, No. 14. pp. 1369-1375.

Bibtex

@article{7d3f56cae614454186954f7893c37f6e,
title = "Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8",
abstract = "The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the structure-based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays. The inhibitor has significantly lower affinity towards KDM2 enzymes (the phylogenetically closest subfamily), and to KDM3 and KDM6 subfamilies. Selectivity is only marginal towards an enzyme from the KDM4 family, which shares histone tail specificity with PHF8. It is a substrate of KDM5B, thus implying that the free N terminus is not part of the KDM5 enzyme substrate recognition machinery. The cyclic peptide's ability to penetrate cells is achieved by incorporation of a sequence derived from HIV Tat. The derived cyclic peptide can be used as a starting compound in the search for potent and selective PHF8 inhibitors.",
keywords = "cyclic peptide, epigenetics, histone demethylase, inhibitors, peptides, PHF8",
author = "Jerzy Dorosz and Lars Olsen and Seger, {Signe Teuber} and Cornelia Steinhauer and Giorgos Bouras and Charlotte Helgstrand and Anders Wiuf and Michael Gajhede",
year = "2017",
month = "7",
day = "18",
doi = "10.1002/cbic.201700109",
language = "English",
volume = "18",
pages = "1369--1375",
journal = "ChemBioChem",
issn = "1439-4227",
publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",
number = "14",

}

RIS

TY - JOUR

T1 - Structure-Based Design of a New Scaffold for Cell-Penetrating Peptidic Inhibitors of the Histone Demethylase PHF8

AU - Dorosz, Jerzy

AU - Olsen, Lars

AU - Seger, Signe Teuber

AU - Steinhauer, Cornelia

AU - Bouras, Giorgos

AU - Helgstrand, Charlotte

AU - Wiuf, Anders

AU - Gajhede, Michael

PY - 2017/7/18

Y1 - 2017/7/18

N2 - The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the structure-based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays. The inhibitor has significantly lower affinity towards KDM2 enzymes (the phylogenetically closest subfamily), and to KDM3 and KDM6 subfamilies. Selectivity is only marginal towards an enzyme from the KDM4 family, which shares histone tail specificity with PHF8. It is a substrate of KDM5B, thus implying that the free N terminus is not part of the KDM5 enzyme substrate recognition machinery. The cyclic peptide's ability to penetrate cells is achieved by incorporation of a sequence derived from HIV Tat. The derived cyclic peptide can be used as a starting compound in the search for potent and selective PHF8 inhibitors.

AB - The histone demethylase PHF8 catalyzes demethylation of mono- and di-methylated Lys9 on histone H3 (H3K9me1/2), and is a transcriptional activator involved in the development and cancer. Affinity and specificity of PHF8 towards H3K9me2 is affected by interaction with both the catalytic domain and a PHD reader domain. The latter specifically recognizes tri-methylated Ly4 on histone H3. A fragment of the histone H3 tail with tri-methylated Lys4 was used as a template for the structure-based design of a cyclic, cell-penetrating peptide that exhibits micromolar binding affinity to PHF8 in biochemical assays. The inhibitor has significantly lower affinity towards KDM2 enzymes (the phylogenetically closest subfamily), and to KDM3 and KDM6 subfamilies. Selectivity is only marginal towards an enzyme from the KDM4 family, which shares histone tail specificity with PHF8. It is a substrate of KDM5B, thus implying that the free N terminus is not part of the KDM5 enzyme substrate recognition machinery. The cyclic peptide's ability to penetrate cells is achieved by incorporation of a sequence derived from HIV Tat. The derived cyclic peptide can be used as a starting compound in the search for potent and selective PHF8 inhibitors.

KW - cyclic peptide

KW - epigenetics

KW - histone demethylase

KW - inhibitors

KW - peptides

KW - PHF8

U2 - 10.1002/cbic.201700109

DO - 10.1002/cbic.201700109

M3 - Journal article

C2 - 28430394

AN - SCOPUS:85020401972

VL - 18

SP - 1369

EP - 1375

JO - ChemBioChem

JF - ChemBioChem

SN - 1439-4227

IS - 14

ER -

ID: 185503838