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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Letter Article

A Cyclic Tripeptide-based Human SIRT3 Inhibitor

Author(s): Bo Wu, Tianli Liu and Weiping Zheng*

Volume 21, Issue 10, 2024

Published on: 12 May, 2023

Page: [1611 - 1616] Pages: 6

DOI: 10.2174/1570180820666230418114000

Price: $65

Abstract

Background: Among the seven human sirtuins SIRT1-7, SIRT3 is not lesser functionally understood. However, the identification of its inhibitors has not been quite a success.

Objective: In the current study, we intended to see if we were able to develop cyclic tripeptide-based human SIRT3 inhibitors that would harbor the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead Ne-thioacetyl-lysine.

Methods: In the current study, we prepared the corresponding N-terminus-to-side chain cyclic analog of two of our previously reported linear tripeptidic human SIRT3 inhibitors whose chemical structures both harbor the catalytic mechanism-based pan-SIRT1/2/3 inhibitory warhead N(epsilon)-thioacetyl-lysine at the central position and subjected the analogs to the same sirtuin inhibition assay under the same assay condition as those employed previously in our laboratory for the two parent linear tripeptidic SIRT3 inhibitors.

Results: We found that analog 2 exhibited an enhanced SIRT3 inhibitory potency than its linear tripeptidic parent (i.e. compound 2a) and displayed a SIRT3 inhibitory IC50 value of ~340 nM which is smaller than its inhibitory IC50 values against other sirtuins with the following folds: ~2-fold versus SIRT1, ~7.7- fold versus SIRT2, and >68-353-fold versus SIRT5-7.

Conclusion: The successful identification of the human SIRT3 inhibitor 2 in the current study would help the further functional dissection and pharmacological exploitation of the SIRT3 deacetylation reaction.

« Previous Next »
[1]
Greiss, S.; Gartner, A. Sirtuin/Sir2 phylogeny, evolutionary considerations and structural conservation. Mol. Cells, 2009, 28(5), 407-415.
[http://dx.doi.org/10.1007/s10059-009-0169-x] [PMID: 19936627]
[2]
Teixeira, C.S.S.; Cerqueira, N.M.F.S.A.; Gomes, P.; Sousa, S.F. A molecular perspective on sirtuin activity. Int. J. Mol. Sci., 2020, 21(22), 8609.
[http://dx.doi.org/10.3390/ijms21228609] [PMID: 33203121]
[3]
Martínez-Redondo, P.; Vaquero, A. The diversity of histone versus nonhistone sirtuin substrates. Genes Cancer, 2013, 4(3-4), 148-163.
[http://dx.doi.org/10.1177/1947601913483767] [PMID: 24020006]
[4]
Bheda, P.; Jing, H.; Wolberger, C.; Lin, H. The substrate specificity of sirtuins. Annu. Rev. Biochem., 2016, 85(1), 405-429.
[http://dx.doi.org/10.1146/annurev-biochem-060815-014537] [PMID: 27088879]
[5]
Chen, B.; Zang, W.; Wang, J.; Huang, Y.; He, Y.; Yan, L.; Liu, J.; Zheng, W. The chemical biology of sirtuins. Chem. Soc. Rev., 2015, 44(15), 5246-5264.
[http://dx.doi.org/10.1039/C4CS00373J] [PMID: 25955411]
[6]
Hu, X.; Zheng, W. Chemical probes in sirtuin research. Prog. Mol. Biol. Transl. Sci., 2018, 154, 1-24.
[http://dx.doi.org/10.1016/bs.pmbts.2017.11.014] [PMID: 29413174]
[7]
Rajabi, N.; Galleano, I.; Madsen, A.S.; Olsen, C.A. Targeting sirtuins: Substrate specificity and inhibitor design. Prog. Mol. Biol. Transl. Sci., 2018, 154, 25-69.
[http://dx.doi.org/10.1016/bs.pmbts.2017.11.003] [PMID: 29413177]
[8]
Chen, G.; Huang, P.; Hu, C. The role of SIRT2 in cancer: A novel therapeutic target. Int. J. Cancer, 2020, 147(12), 3297-3304.
[http://dx.doi.org/10.1002/ijc.33118] [PMID: 32449165]
[9]
Klein, M.A.; Denu, J.M. Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators. J. Biol. Chem., 2020, 295(32), 11021-11041.
[http://dx.doi.org/10.1074/jbc.REV120.011438] [PMID: 32518153]
[10]
Kosciuk, T.; Wang, M.; Hong, J.Y.; Lin, H. Updates on the epigenetic roles of sirtuins. Curr. Opin. Chem. Biol., 2019, 51, 18-29.
[http://dx.doi.org/10.1016/j.cbpa.2019.01.023] [PMID: 30875552]
[11]
Kumar, S.; Lombard, D.B. Functions of the sirtuin deacylase SIRT5 in normal physiology and pathobiology. Crit. Rev. Biochem. Mol. Biol., 2018, 53(3), 311-334.
[http://dx.doi.org/10.1080/10409238.2018.1458071] [PMID: 29637793]
[12]
Li, S.; Zheng, W. Mammalian sirtuins SIRT4 and SIRT7. Prog. Mol. Biol. Transl. Sci., 2018, 154, 147-168.
[http://dx.doi.org/10.1016/bs.pmbts.2017.11.001] [PMID: 29413176]
[13]
Zhang, J.; Xiang, H.; Liu, J.; Chen, Y.; He, R.R.; Liu, B. Mitochondrial sirtuin 3: New emerging biological function and therapeutic target. Theranostics, 2020, 10(18), 8315-8342.
[http://dx.doi.org/10.7150/thno.45922] [PMID: 32724473]
[14]
Dai, H.; Sinclair, D.A.; Ellis, J.L.; Steegborn, C. Sirtuin activators and inhibitors: Promises, achievements, and challenges. Pharmacol. Ther., 2018, 188, 140-154.
[http://dx.doi.org/10.1016/j.pharmthera.2018.03.004] [PMID: 29577959]
[15]
Jiang, Y.; Liu, J.; Chen, D.; Yan, L.; Zheng, W. Sirtuin inhibition: Strategies, inhibitors, and therapeutic potential. Trends Pharmacol. Sci., 2017, 38(5), 459-472.
[http://dx.doi.org/10.1016/j.tips.2017.01.009] [PMID: 28389129]
[16]
Liu, G.; Chen, H.; Liu, H.; Zhang, W.; Zhou, J. Emerging roles of SIRT6 in human diseases and its modulators. Med. Res. Rev., 2021, 41(2), 1089-1137.
[http://dx.doi.org/10.1002/med.21753] [PMID: 33325563]
[17]
Schiedel, M.; Robaa, D.; Rumpf, T.; Sippl, W.; Jung, M. The current state of NAD+-dependent histone deacetylases (sirtuins) as novel therapeutic targets. Med. Res. Rev., 2018, 38(1), 147-200.
[http://dx.doi.org/10.1002/med.21436] [PMID: 28094444]
[18]
Wang, T.; Xu, Z.; Lu, Y.; Shi, J.; Liu, W.; Zhang, C.; Jiang, Z.; Qi, B.; Bai, L. Recent progress on the discovery of sirt2 inhibitors for the treatment of various cancers. Curr. Top. Med. Chem., 2019, 19(12), 1051-1058.
[http://dx.doi.org/10.2174/1568026619666190510103416] [PMID: 31074370]
[19]
Wang, Y.; He, J.; Liao, M.; Hu, M.; Li, W.; Ouyang, H.; Wang, X.; Ye, T.; Zhang, Y.; Ouyang, L. An overview of sirtuins as potential therapeutic target: Structure, function and modulators. Eur. J. Med. Chem., 2019, 161, 48-77.
[http://dx.doi.org/10.1016/j.ejmech.2018.10.028] [PMID: 30342425]
[20]
Li, R.; Yan, L.; Sun, X.; Zheng, W. A bicyclic pentapeptide-based highly potent and selective pan-SIRT1/2/3 inhibitor harboring Nε-thioacetyl-lysine. Bioorg. Med. Chem., 2020, 28(7), 115356.
[http://dx.doi.org/10.1016/j.bmc.2020.115356] [PMID: 32067892]
[21]
Chen, D.; Zheng, W. Cyclic peptide-based potent and selective SIRT1/2 dual inhibitors harboring Nε-thioacetyl-lysine. Bioorg. Med. Chem. Lett., 2016, 26(21), 5234-5239.
[http://dx.doi.org/10.1016/j.bmcl.2016.09.055] [PMID: 27707605]
[22]
Hui, Q.; Li, X.; Fan, W.; Gao, C.; Zhang, L.; Qin, H.; Wei, L.; Zhang, L. Discovery of 2-(4-acrylamidophenyl)-quinoline-4-carboxylic acid derivatives as potent SIRT3 inhibitors. Front Chem., 2022, 10, 880067.
[http://dx.doi.org/10.3389/fchem.2022.880067] [PMID: 35433629]
[23]
Loharch, S.; Chhabra, S.; Kumar, A.; Swarup, S.; Parkesh, R. Discovery and characterization of small molecule SIRT3-specific inhibitors as revealed by mass spectrometry. Bioorg. Chem., 2021, 110, 104768.
[http://dx.doi.org/10.1016/j.bioorg.2021.104768] [PMID: 33676042]
[24]
Troelsen, K.S.; Bæk, M.; Nielsen, A.L.; Madsen, A.S.; Rajabi, N.; Olsen, C.A. Mitochondria-targeted inhibitors of the human SIRT3 lysine deacetylase. RSC Chem. Biol., 2021, 2(2), 627-635.
[http://dx.doi.org/10.1039/D0CB00216J] [PMID: 34458804]
[25]
Goodman, M.; Ro, S. Peptidomimetics for drug design. In: Burger’s medicinal chemistry and drug discovery: Principles and practice; Wolff, M.E., Ed.; John Wiley & Sons: Hoboken, 1995; Vol. 1, pp. 803-861.
[26]
Chen, B.; Wang, J.; Huang, Y.; Zheng, W. Human SIRT3 tripeptidic inhibitors containing Nε-thioacetyl-lysine. Bioorg. Med. Chem. Lett., 2015, 25(17), 3481-3487.
[http://dx.doi.org/10.1016/j.bmcl.2015.07.008] [PMID: 26220157]
[27]
Tickler, A.K.; Barrow, C.J.; Wade, J.D. Improved preparation of amyloid peptides using DBU as Nalpha-Fmoc deprotection reagent. J. Pept. Sci., 2001, 7(9), 488-494.
[http://dx.doi.org/10.1002/psc.342] [PMID: 11587187]
[28]
Li, S.; Wu, B.; Zheng, W. Cyclic tripeptide-based potent human SIRT7 inhibitors. Bioorg. Med. Chem. Lett., 2019, 29(3), 461-465.
[http://dx.doi.org/10.1016/j.bmcl.2018.12.023] [PMID: 30578034]
[29]
Hirsch, B.M.; Gallo, C.A.; Du, Z.; Wang, Z.; Zheng, W. Discovery of potent, proteolytically stable, and cell permeable human sirtuin peptidomimetic inhibitors containing Nε-thioacetyl-lysine. MedChemComm, 2010, 1(3), 233-238.
[http://dx.doi.org/10.1039/c0md00089b]
[30]
Hong, J.Y.; Zhang, X.; Lin, H. HPLC-based enzyme assays for sirtuins. Methods Mol. Biol., 2018, 1813, 225-234.
[http://dx.doi.org/10.1007/978-1-4939-8588-3_15] [PMID: 30097871]
[31]
Dixon, M. The determination of enzyme inhibitor constants. Biochem. J., 1953, 55(1), 170-171.
[http://dx.doi.org/10.1042/bj0550170] [PMID: 13093635]

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