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Development of Peptide-Based Sirtuin Defatty-Acylase Inhibitors Identified by the Fluorescence Probe, SFP3, That Can Efficiently Measure Defatty-Acylase Activity of Sirtuin

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    Development of Peptide-Based Sirtuin Defatty-Acylase Inhibitors Identified by the Fluorescence Probe, SFP3, That Can Efficiently Measure Defatty-Acylase Activity of Sirtuin
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    • Mitsuyasu Kawaguchi
      Mitsuyasu Kawaguchi
      Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan
      More by Mitsuyasu Kawaguchi
    • Naoya Ieda
      Naoya Ieda
      Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan
      More by Naoya Ieda
    • Hidehiko Nakagawa*
      Hidehiko Nakagawa
      Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan
      *E-mail: [email protected]. Tel: +81-52-836-3407. Fax: +81-52-836-3407.
      More by Hidehiko Nakagawa
      Orcidhttp://orcid.org/0000-0001-8435-4401
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2019, 62, 11, 5434–5452
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    https://doi.org/10.1021/acs.jmedchem.9b00315
    Published May 22, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    Sirtuins (SIRTs) are a family of nicotinamide adenine dinucleotide-dependent histone deacetylases that serve as epigenetic regulators of many physiological processes. Recent studies have shown that in addition to their well-known deacetylase activity, sirtuins also exhibit deacylase activity, such as demyristoylase activity. Here, we show that our previously reported sirtuin fluorescence probe, SFP3, can measure the defatty-acylase activity of SIRT1–3, enabling selective assay of the deacylase activity. We further utilized this finding to develop the first inhibitors of SIRT2 defatty-acylase activity. Notably, most previously reported sirtuin inhibitors, including compound TM, AGK2, and SirReal2, showed almost no SIRT2 defatty-acylase-inhibitory activity, but are essentially specific deacetylase inhibitors. These results suggest that the active sites catalyzing the deacetylase and defatty-acylase activities of sirtuins may be independent.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.9b00315.

    • Absorbance spectra of synthesized compounds; SIRT inhibition curves of synthesized compounds and known SIRT2 inhibitors toward SIRT1–3, and 6 in SFP3, p53(Myr)-AMC, and FLUOR DE LYS SIRT2 kit assays; Michaelis–Menten plots of H4K16-Ac and H4K16-Myr against SIRT2; SIRT2 deacetylase inhibition assay using H4K16-Ac peptide; cell viability assay using HeLa cells; competition analysis of S2DMi-6 and S2DMi-9 with NAD+; purity data of all synthesized compounds by HPLC and enantiomerical purity data of compounds 1–6 (PDF)

    • Molecular formula strings and enzyme inhibition data (CSV)

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    This article is cited by 17 publications.

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    3. Yuya Nakajima, Mitsuyasu Kawaguchi, Naoya Ieda, Hidehiko Nakagawa. A Set of Highly Sensitive Sirtuin Fluorescence Probes for Screening Small-Molecular Sirtuin Defatty-Acylase Inhibitors. ACS Medicinal Chemistry Letters 2021, 12 (4) , 617-624. https://doi.org/10.1021/acsmedchemlett.1c00010
    4. Jun Young Hong, Hui Jing, Ian Robert Price, Ji Cao, Jessica Jingyi Bai, Hening Lin. Simultaneous Inhibition of SIRT2 Deacetylase and Defatty-Acylase Activities via a PROTAC Strategy. ACS Medicinal Chemistry Letters 2020, 11 (11) , 2305-2311. https://doi.org/10.1021/acsmedchemlett.0c00423
    5. David Bi, Jie Yang, Jun Young Hong, Prashit Parikh, Nicole Hinds, Joseph Infanti, Hening Lin, Brian P. Weiser. Substrate-Dependent Modulation of SIRT2 by a Fluorescent Probe, 1-Aminoanthracene. Biochemistry 2020, 59 (40) , 3869-3878. https://doi.org/10.1021/acs.biochem.0c00564
    6. Weiping Zheng. The (patho)physiological roles of the individual deacylase activities of a sirtuin. Chemical Biology & Drug Design 2024, 103 (2) https://doi.org/10.1111/cbdd.14460
    7. Cora N. Betsinger, Joshua L. Justice, Matthew D. Tyl, Julia E. Edgar, Hanna G. Budayeva, Yaa F. Abu, Ileana M. Cristea, . Sirtuin 2 promotes human cytomegalovirus replication by regulating cell cycle progression. mSystems 2023, 8 (6) https://doi.org/10.1128/msystems.00510-23
    8. Junxin Xue, Xuben Hou, Hao Fang. Structure, functions, and recent advances in the development of SIRT2 inhibitors. Pharmaceutical Science Advances 2023, 1 (2) , 100010. https://doi.org/10.1016/j.pscia.2023.100010
    9. Mitsuyasu Kawaguchi, Yuya Nakajima, Hidehiko Nakagawa. Development of Sirtuin Fluorescence Probes and Medicinal Chemistry Research Targeting SIRT Family. Journal of Synthetic Organic Chemistry, Japan 2022, 80 (9) , 831-842. https://doi.org/10.5059/yukigoseikyokaishi.80.831
    10. Pan Wang, Di Chen, Jian-xiong An, Shu-xian Lin, Ting Liu, Yan Li, Lei Chen, Bin He. Development of a single-step fluorogenic sirtuin assay and its applications for high-throughput screening. Organic & Biomolecular Chemistry 2022, 20 (6) , 1243-1252. https://doi.org/10.1039/D1OB02347K
    11. Anna-Theresa Blasl, Sabrina Schulze, Chuan Qin, Leonie G. Graf, Robert Vogt, Michael Lammers. Post-translational lysine ac(et)ylation in health, ageing and disease. Biological Chemistry 2022, 403 (2) , 151-194. https://doi.org/10.1515/hsz-2021-0139
    12. Kan'ichiro Ishiuchi, Akiho Nagumo, Mitsuyasu Kawaguchi, Honoka Furuyashiki, Hidehiko Nakagawa, Dai Hirose. Mariannamides C and D, Two New Lipohexapeptides, Isolated from Mariannaea Elegans NBRC102301. SSRN Electronic Journal 2022, 40 https://doi.org/10.2139/ssrn.4143072
    13. Kan'ichiro Ishiuchi, Akiho Nagumo, Mitsuyasu Kawaguchi, Honoka Furuyashiki, Hidehiko Nakagawa, Dai Hirose. Stereochemistries of Mariannamides C and D, Two Lipohexapeptides, Isolated from Mariannaea elegans NBRC102301. HETEROCYCLES 2022, 104 (10) , 1822. https://doi.org/10.3987/COM-22-14728
    14. Jun Young Hong, Joel Cassel, Jie Yang, Hening Lin, Brian P. Weiser. High‐Throughput Screening Identifies Ascorbyl Palmitate as a SIRT2 Deacetylase and Defatty‐Acylase Inhibitor. ChemMedChem 2021, 16 (22) , 3484-3494. https://doi.org/10.1002/cmdc.202100343
    15. Rihan Hai, Liuer He, Guang Shu, Gang Yin. Characterization of Histone Deacetylase Mechanisms in Cancer Development. Frontiers in Oncology 2021, 11 https://doi.org/10.3389/fonc.2021.700947
    16. Alexander L. Nielsen, Nima Rajabi, Norio Kudo, Kathrine Lundø, Carlos Moreno-Yruela, Michael Bæk, Martin Fontenas, Alessia Lucidi, Andreas S. Madsen, Minoru Yoshida, Christian A. Olsen. Mechanism-based inhibitors of SIRT2: structure–activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration. RSC Chemical Biology 2021, 2 (2) , 612-626. https://doi.org/10.1039/D0CB00036A
    17. Mitsuyasu Kawaguchi, Hidehiko Nakagawa. Live-Cell Imaging of Sirtuin Activity Using a One-Step Fluorescence Probe. 2021, 155-168. https://doi.org/10.1007/978-1-0716-1258-3_14
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2019, 62, 11, 5434–5452
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.9b00315
    Published May 22, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

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