Review of the article „Cyclic peptide-based sirtuin substrates“, verified by Publons, Web of Science
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2018
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Background: Sirtuins refer to a family of intracellular enzymes able to catalyze the -
nicotinamide adenine dinucleotide (-NAD+)-dependent N-acyl-lysine deacylation on histone
and non-histone proteins in organisms from all the three kingdoms of life (i.e. bacteria,
archaea, and eukarya). The sirtuin-catalyzed deacylation plays an important regulatory role in
multiple crucial cellular processes, e.g. transcription, metabolism, and DNA damage repair.
This enzymatic reaction has been regarded as a novel therapeutic target for multiple human
diseases such as cancer, metabolic and neurodegenerative diseases. Therefore, chemical
modulators (activators and inhibitors) for the sirtuin-catalyzed deacylation have been actively
pursued during past few years, and quite a few in vitro sirtuin substrates have been developed
and employed on in vitro screening platforms for such chemical modulators.
Objective: Since the currently existing in vitro sirtuin substrates are primarily linear p...eptidebased,
we would like to see if cyclic peptide-based superior sirtuin substrates could be
developed because cyclic peptides generally have an enhanced target binding affinity than
linear peptides.
Methods: Four side chain-to-side chain cyclic peptides (i.e. the 5-mer 5-7 and the 4-mer 8)
harboring N-acetyl-lysine or N-myristoyl-lysine were designed, synthesized by the N-9-
fluorenylmethoxycarbonyl (Fmoc) chemistry-based solid phase peptide synthesis (SPPS) on
the Rink amide resin, purified by the semi-preparative reversed-phase high performance
liquid chromatography (RP-HPLC), characterized by the high-resolution mass spectrometry
(HRMS); and were evaluated for their in vitro SIRT1/2/3 substrate activities and their in vitro
proteolytic stability.
Results: As judged by kcat/KM ratios, cyclic peptides 5-8 behaved as superior in vitro SIRT1 or
SIRT3 substrates to the best linear hexapeptide-based in vitro SIRT1 or SIRT3 substrates
reported in current literature. Cyclic peptides 5-8 are also proteolytically much more stable
than a linear pentapeptide control.
Conclusion: The findings from this proof-of-concept study indicate that it is possible to
develop cyclic peptide-based sirtuin substrates with decent kcat/KM ratios and proteolytic
stability. Since cyclic peptides generally also have an enhanced cell permeability than linear
peptides, the cyclic peptide-based sirtuin substrates may also be exploited to assess the
intracellular sirtuin deacylation activities when combined with the use of the
potent/selective/cell permeable sirtuin deacylation inhibitors.
Извор:
Medicinal Chemistry, 2018, 1/BMS-MC-2018-276-30Колекције
Институција/група
Mašinski fakultetTY - JOUR AU - Jovanović, Tamara PY - 2018 UR - https://machinery.mas.bg.ac.rs/handle/123456789/6163 AB - Background: Sirtuins refer to a family of intracellular enzymes able to catalyze the - nicotinamide adenine dinucleotide (-NAD+)-dependent N-acyl-lysine deacylation on histone and non-histone proteins in organisms from all the three kingdoms of life (i.e. bacteria, archaea, and eukarya). The sirtuin-catalyzed deacylation plays an important regulatory role in multiple crucial cellular processes, e.g. transcription, metabolism, and DNA damage repair. This enzymatic reaction has been regarded as a novel therapeutic target for multiple human diseases such as cancer, metabolic and neurodegenerative diseases. Therefore, chemical modulators (activators and inhibitors) for the sirtuin-catalyzed deacylation have been actively pursued during past few years, and quite a few in vitro sirtuin substrates have been developed and employed on in vitro screening platforms for such chemical modulators. Objective: Since the currently existing in vitro sirtuin substrates are primarily linear peptidebased, we would like to see if cyclic peptide-based superior sirtuin substrates could be developed because cyclic peptides generally have an enhanced target binding affinity than linear peptides. Methods: Four side chain-to-side chain cyclic peptides (i.e. the 5-mer 5-7 and the 4-mer 8) harboring N-acetyl-lysine or N-myristoyl-lysine were designed, synthesized by the N-9- fluorenylmethoxycarbonyl (Fmoc) chemistry-based solid phase peptide synthesis (SPPS) on the Rink amide resin, purified by the semi-preparative reversed-phase high performance liquid chromatography (RP-HPLC), characterized by the high-resolution mass spectrometry (HRMS); and were evaluated for their in vitro SIRT1/2/3 substrate activities and their in vitro proteolytic stability. Results: As judged by kcat/KM ratios, cyclic peptides 5-8 behaved as superior in vitro SIRT1 or SIRT3 substrates to the best linear hexapeptide-based in vitro SIRT1 or SIRT3 substrates reported in current literature. Cyclic peptides 5-8 are also proteolytically much more stable than a linear pentapeptide control. Conclusion: The findings from this proof-of-concept study indicate that it is possible to develop cyclic peptide-based sirtuin substrates with decent kcat/KM ratios and proteolytic stability. Since cyclic peptides generally also have an enhanced cell permeability than linear peptides, the cyclic peptide-based sirtuin substrates may also be exploited to assess the intracellular sirtuin deacylation activities when combined with the use of the potent/selective/cell permeable sirtuin deacylation inhibitors. T2 - Medicinal Chemistry T1 - Review of the article „Cyclic peptide-based sirtuin substrates“, verified by Publons, Web of Science EP - 30 SP - 1/BMS-MC-2018-276 UR - https://hdl.handle.net/21.15107/rcub_machinery_6163 ER -
@article{ author = "Jovanović, Tamara", year = "2018", abstract = "Background: Sirtuins refer to a family of intracellular enzymes able to catalyze the - nicotinamide adenine dinucleotide (-NAD+)-dependent N-acyl-lysine deacylation on histone and non-histone proteins in organisms from all the three kingdoms of life (i.e. bacteria, archaea, and eukarya). The sirtuin-catalyzed deacylation plays an important regulatory role in multiple crucial cellular processes, e.g. transcription, metabolism, and DNA damage repair. This enzymatic reaction has been regarded as a novel therapeutic target for multiple human diseases such as cancer, metabolic and neurodegenerative diseases. Therefore, chemical modulators (activators and inhibitors) for the sirtuin-catalyzed deacylation have been actively pursued during past few years, and quite a few in vitro sirtuin substrates have been developed and employed on in vitro screening platforms for such chemical modulators. Objective: Since the currently existing in vitro sirtuin substrates are primarily linear peptidebased, we would like to see if cyclic peptide-based superior sirtuin substrates could be developed because cyclic peptides generally have an enhanced target binding affinity than linear peptides. Methods: Four side chain-to-side chain cyclic peptides (i.e. the 5-mer 5-7 and the 4-mer 8) harboring N-acetyl-lysine or N-myristoyl-lysine were designed, synthesized by the N-9- fluorenylmethoxycarbonyl (Fmoc) chemistry-based solid phase peptide synthesis (SPPS) on the Rink amide resin, purified by the semi-preparative reversed-phase high performance liquid chromatography (RP-HPLC), characterized by the high-resolution mass spectrometry (HRMS); and were evaluated for their in vitro SIRT1/2/3 substrate activities and their in vitro proteolytic stability. Results: As judged by kcat/KM ratios, cyclic peptides 5-8 behaved as superior in vitro SIRT1 or SIRT3 substrates to the best linear hexapeptide-based in vitro SIRT1 or SIRT3 substrates reported in current literature. Cyclic peptides 5-8 are also proteolytically much more stable than a linear pentapeptide control. Conclusion: The findings from this proof-of-concept study indicate that it is possible to develop cyclic peptide-based sirtuin substrates with decent kcat/KM ratios and proteolytic stability. Since cyclic peptides generally also have an enhanced cell permeability than linear peptides, the cyclic peptide-based sirtuin substrates may also be exploited to assess the intracellular sirtuin deacylation activities when combined with the use of the potent/selective/cell permeable sirtuin deacylation inhibitors.", journal = "Medicinal Chemistry", title = "Review of the article „Cyclic peptide-based sirtuin substrates“, verified by Publons, Web of Science", pages = "30-1/BMS-MC-2018-276", url = "https://hdl.handle.net/21.15107/rcub_machinery_6163" }
Jovanović, T.. (2018). Review of the article „Cyclic peptide-based sirtuin substrates“, verified by Publons, Web of Science. in Medicinal Chemistry, 1/BMS-MC-2018-276-30. https://hdl.handle.net/21.15107/rcub_machinery_6163
Jovanović T. Review of the article „Cyclic peptide-based sirtuin substrates“, verified by Publons, Web of Science. in Medicinal Chemistry. 2018;:1/BMS-MC-2018-276-30. https://hdl.handle.net/21.15107/rcub_machinery_6163 .
Jovanović, Tamara, "Review of the article „Cyclic peptide-based sirtuin substrates“, verified by Publons, Web of Science" in Medicinal Chemistry (2018):1/BMS-MC-2018-276-30, https://hdl.handle.net/21.15107/rcub_machinery_6163 .