Top Med Chem (2020) 33: 29–54
DOI: 10.1007/7355_2019_69
© Springer Nature Switzerland AG 2019
Published online: 28 November 2019
Hydroxamic Acid-Containing Peptides
in the Study of Histone Deacetylases
Carlos Moreno-Yruela and Christian A. Olsen
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2 Hydroxamic Acid: A Transition State Mimic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3 Synthesis of Hydroxamic Acid-Containing Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
4 Structure-Activity Relationship of Macrocyclic HDAC Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 36
4.1 Biological Activity of Selected Inhibitors . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . .. 43
5 Chemical Tools for the Study of HDAC Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
6 Conclusions and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Abstract Histone deacetylases (HDACs) are ubiquitous enzymes that remove ε-Nacetyl-lysine posttranslational modifications (PTMs) on histone tails. The resulting
PTM landscape affects chromatin packing and recruitment of transcription factors, in
turn playing an indirect role in regulation of gene expression. Deregulation of the
activity of these hydrolases has been associated with several complex diseases. Thus,
HDAC inhibitors have been approved for cancer treatment and are being studied
against inflammation, neurodegeneration, and autoimmune disorders among others.
The role of each of the 11 Zn
2+ -dependent HDACs has not yet been elucidated,
mainly due to their structural similarity and, in part, due to the absence of isotypeselective probes. Such selectivity may be achievable by targeting features outside of
the active site pocket, which is highly conserved. Peptides, which may cover larger
areas than small molecules, may become useful chemical tools able to reach
unexplored areas of the protein surface to achieve selectivity. In addition, by
incorporating hydroxamic acid-containing lysine mimics in their structure, strong
binding to the catalytic cavity is achieved. Furthermore, such molecules present
similarities to the native substrates, which could be exploited for determining targets
of their deacetylase activity. Therefore, hydroxamic acid-containing peptides have
C. Moreno-Yruela and C. A. Olsen (*)
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,
University of Copenhagen, Copenhagen, Denmark
e-mail: cao@sund.ku.dk
DOI: 10.1007/7355_2019_69
© Springer Nature Switzerland AG 2019
Published online: 28 November 2019
Hydroxamic Acid-Containing Peptides
in the Study of Histone Deacetylases
Carlos Moreno-Yruela and Christian A. Olsen
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
2 Hydroxamic Acid: A Transition State Mimic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3 Synthesis of Hydroxamic Acid-Containing Peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
4 Structure-Activity Relationship of Macrocyclic HDAC Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 36
4.1 Biological Activity of Selected Inhibitors . . . . . . . . . . . . . . . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . .. 43
5 Chemical Tools for the Study of HDAC Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
6 Conclusions and Future Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Abstract Histone deacetylases (HDACs) are ubiquitous enzymes that remove ε-Nacetyl-lysine posttranslational modifications (PTMs) on histone tails. The resulting
PTM landscape affects chromatin packing and recruitment of transcription factors, in
turn playing an indirect role in regulation of gene expression. Deregulation of the
activity of these hydrolases has been associated with several complex diseases. Thus,
HDAC inhibitors have been approved for cancer treatment and are being studied
against inflammation, neurodegeneration, and autoimmune disorders among others.
The role of each of the 11 Zn
2+ -dependent HDACs has not yet been elucidated,
mainly due to their structural similarity and, in part, due to the absence of isotypeselective probes. Such selectivity may be achievable by targeting features outside of
the active site pocket, which is highly conserved. Peptides, which may cover larger
areas than small molecules, may become useful chemical tools able to reach
unexplored areas of the protein surface to achieve selectivity. In addition, by
incorporating hydroxamic acid-containing lysine mimics in their structure, strong
binding to the catalytic cavity is achieved. Furthermore, such molecules present
similarities to the native substrates, which could be exploited for determining targets
of their deacetylase activity. Therefore, hydroxamic acid-containing peptides have
C. Moreno-Yruela and C. A. Olsen (*)
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences,
University of Copenhagen, Copenhagen, Denmark
e-mail: cao@sund.ku.dk