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Hydroxamic acid-modified peptide microarrays for profiling isozyme-selective interactions and inhibition of histone deacetylases

preprint
revised on 18.11.2020, 19:35 and posted on 19.11.2020, 06:11 by Carlos Moreno-Yruela, Michael Bæk,, Adela-Eugenie Vrsanova, Hans M. Maric, Clemens Schulte, Christian Adam Olsen
Histones control gene expression by regulating chromatin structure and function. The posttranslational modifications (PTMs) on the side chains of histones form the epigenetic landscape, which is tightly controlled by epigenetic modulator enzymes and further recognized by so-called reader domains. Histone microarrays have been widely applied to investigate histone–reader interactions, but not the transient interactions of Zn2+-dependent histone deacetylase (HDAC) eraser enzymes. Here, we synthesize hydroxamic acid-modified histone peptides and use them in femtomolar microarrays for the direct capture and detection of the four class I HDAC isozymes. Follow-up functional assays in solution demonstrate their suitability to discover HDAC substrates and inhibitors with nanomolar potency and activity in cellular assays. We conclude that similar hydroxamic acid-modified histone peptide microarrays and libraries could find broad application to identify class I HDAC isozyme-specific substrates and facilitate the development of isozyme-selective HDAC inhibitors and probes

Funding

Carlsbergfondet (2013-01-0333)

Carlsbergfoncet (CF18-0442)

European Research Council (ERC-CoG-725172 – SIRFUNCT)

Lundbeck Foundation (R289-2018-2074)

History

Email Address of Submitting Author

cao@sund.ku.dk

Institution

University of Copenhagen

Country

Denmark

ORCID For Submitting Author

0000-0002-2953-8942

Declaration of Conflict of Interest

The authors declare no conflicts of interest

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