Synthesis and characterisation of substrate-based peptides as inhibitors of histone demethylase KDM4C

Simon D Nielsen; Ulrike Leurs; Magnus Bergner; Silvia Amor Barris; Kanchan Devkota; Kamilla Meyer; Daniella Iaria; Jack McCaughan; Brian Lohse; Jesper L Kristensen; Rasmus Prætorius Clausen

doi:10.2174/0929866523666160613210831

Synthesis and characterisation of substrate-based peptides as inhibitors of histone demethylase KDM4C

Simon D Nielsen, Ulrike Leurs, Magnus Bergner, Silvia Amor Barris, Kanchan Devkota, Kamilla Meyer, Daniella Iaria, Jack McCaughan, Brian Lohse, Jesper L Kristensen, Rasmus Prætorius Clausen

Abstract

The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N- Acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups. The click reaction is compatible with free amino acids and this was performed on an azido containing deprotected pentapeptide demonstrating a highly facile and convergent synthetic strategy for making substrate-based inhibitors. One of the 14 peptides showed inhibitory activity at KDM4C demonstrating the need for an iron chelator in the pentapeptide series.

Original language	English
Journal	Protein and Peptide Letters
Volume	23
Issue number	9
Pages (from-to)	772 - 776
Number of pages	5
ISSN	0929-8665
DOIs	https://doi.org/10.2174/0929866523666160613210831
Publication status	Published - 1 Sept 2016

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title = "Synthesis and characterisation of substrate-based peptides as inhibitors of histone demethylase KDM4C",

abstract = "The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N- Acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups. The click reaction is compatible with free amino acids and this was performed on an azido containing deprotected pentapeptide demonstrating a highly facile and convergent synthetic strategy for making substrate-based inhibitors. One of the 14 peptides showed inhibitory activity at KDM4C demonstrating the need for an iron chelator in the pentapeptide series.",

author = "Nielsen, {Simon D} and Ulrike Leurs and Magnus Bergner and Barris, {Silvia Amor} and Kanchan Devkota and Kamilla Meyer and Daniella Iaria and Jack McCaughan and Brian Lohse and Kristensen, {Jesper L} and Clausen, {Rasmus Pr{\ae}torius}",

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doi = "10.2174/0929866523666160613210831",

language = "English",

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journal = "Protein and Peptide Letters",

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TY - JOUR

T1 - Synthesis and characterisation of substrate-based peptides as inhibitors of histone demethylase KDM4C

AU - Nielsen, Simon D

AU - Leurs, Ulrike

AU - Bergner, Magnus

AU - Barris, Silvia Amor

AU - Devkota, Kanchan

AU - Meyer, Kamilla

AU - Iaria, Daniella

AU - McCaughan, Jack

AU - Lohse, Brian

AU - Kristensen, Jesper L

AU - Clausen, Rasmus Prætorius

PY - 2016/9/1

Y1 - 2016/9/1

N2 - The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N- Acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups. The click reaction is compatible with free amino acids and this was performed on an azido containing deprotected pentapeptide demonstrating a highly facile and convergent synthetic strategy for making substrate-based inhibitors. One of the 14 peptides showed inhibitory activity at KDM4C demonstrating the need for an iron chelator in the pentapeptide series.

AB - The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N- Acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups. The click reaction is compatible with free amino acids and this was performed on an azido containing deprotected pentapeptide demonstrating a highly facile and convergent synthetic strategy for making substrate-based inhibitors. One of the 14 peptides showed inhibitory activity at KDM4C demonstrating the need for an iron chelator in the pentapeptide series.

U2 - 10.2174/0929866523666160613210831

DO - 10.2174/0929866523666160613210831

M3 - Journal article

C2 - 27295953

SN - 0929-8665

VL - 23

SP - 772

EP - 776

JO - Protein and Peptide Letters

JF - Protein and Peptide Letters

IS - 9

ER -

Synthesis and characterisation of substrate-based peptides as inhibitors of histone demethylase KDM4C

Abstract

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