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Updated: Dec 26, 2025

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Sensitive fluorogenic substrates for sirtuin deacylase inhibitor discovery.

Ling-Ling Yang1, Hua-Li Wang2, Yu-Hang Yan2

  • 1College of Food and Bioengineering, Xihua University, Sichuan, 610039, PR China.

European Journal of Medicinal Chemistry
|March 13, 2020
PubMed
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This summary is machine-generated.

Researchers developed novel fluorogenic peptide substrates to discover sirtuin (SIRT) inhibitors for treating diseases. New substrates show high sensitivity and enable structural insights, aiding in developing dual-action SIRT5/Bcl-2 cancer inhibitors.

Area of Science:

  • Biochemistry
  • Enzymology
  • Drug Discovery

Background:

  • Sirtuins (SIRTs) are NAD+-dependent enzymes regulating crucial biological processes.
  • SIRT inhibitors show therapeutic potential for various human diseases.
  • Efficient assay platforms are vital for discovering high-quality SIRT inhibitors.

Purpose of the Study:

  • To develop novel fluorogenic peptide substrates for assaying human sirtuin activity.
  • To identify sensitive substrates for specific SIRT isoforms (SIRT1, SIRT2, SIRT3, SIRT5).
  • To provide structural insights into substrate-binding modes and facilitate inhibitor development.

Main Methods:

  • Design and synthesis of 16 new fluorogenic peptide substrates (P1-P16).
  • Enzymatic assays to test substrate sensitivity and kinetic parameters (KM, catalytic efficiency) against SIRT isoforms.
Keywords:
Bcl-2DeacylaseFluorogenic substrateSIRT5Sirtuin

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  • Co-crystallization studies of SIRT5 with sensitive substrates (P13, P15).
  • Inhibitor screening using developed substrates, including validation with isothermal titration calorimetry.

    • Main Results:

    • Identified several sensitive substrates for SIRT1, SIRT2, SIRT3, and SIRT5 with improved kinetic properties and reduced signal interference.
    • Co-crystallization revealed an unexpected binding mode of substrates P13 and P15 with SIRT5.
    • TW-37, a Bcl-2 inhibitor, demonstrated low micromolar inhibition of SIRT5 using the developed assay.

    Conclusions:

    • The new fluorogenic substrates provide an effective platform for SIRT inhibitor discovery.
    • Structural data offers insights into SIRT-substrate interactions, guiding future substrate design.
    • The findings support the development of dual-action SIRT5/Bcl-2 inhibitors for cancer therapy.