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Published on: February 27, 2019
Cyclic Tripeptide-based Potent and Selective Human SIRT5 Inhibitors
Yanhong Jiang1, Weiping Zheng1
1School of Pharmacy, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, Jiangsu Province, China.
Background:
SIRT5 is one of the seven members (SIRT1-7) of the mammalian sirtuin family of protein acyl-lysine deacylase enzymes. In recent years, important regulatory roles of SIRT5 in (patho)physiological conditions (e.g. metabolism and cancer) have been increasingly demonstrated. For a better biological understanding and therapeutic exploitation of the SIRT5- catalyzed deacylation reaction, more effort on identifying potent and selective SIRT5 inhibitors beyond those currently known would be rewarding.
Objective:
In the current study, we would like to see if it would be possible to develop potent and selective SIRT5 inhibitory lead compounds with a novel structural scaffold than those of the currently known potent and selective SIRT5 inhibitors.
Methods:
In the current study, six N-terminus-to-side chain cyclic tripeptides (i.e. 8-13) each harboring the thiourea-type catalytic mechanism-based SIRT5 inhibitory warhead Nε-carboxyethylthiocarbamoyl- lysine as the central residue were designed, synthesized by the Nα-9- fluorenylmethoxycarbonyl (Fmoc) chemistry-based solid phase peptide synthesis (SPPS) on the Rink amide 4-methylbenzhydrylamine (MBHA) resin, purified by the semi-preparative reversedphase high performance liquid chromatography (RP-HPLC), characterized by the high-resolution mass spectrometry (HRMS); and were evaluated by the in vitro sirtuin inhibition assay and the in vitro proteolysis assay.
Results:
Among the cyclic tripeptides 8-13, we found that 10 exhibited a potent (IC50 ~2.2 μM) and selective (≥60-fold over the SIRT1/2/3/6-catalyzed deacylation reactions) inhibition against the SIRT5-catalyzed desuccinylation reaction. Moreover, 10 was found to exhibit a ~42.3-fold stronger SIRT5 inhibition and a greater proteolytic stability than its linear counterpart 14.
Conclusion:
With a novel and modular structural scaffold as compared with those of all the currently reported potent and selective SIRT5 inhibitors, 10 could be also a useful and feasible lead compound for the quest for superior SIRT5 inhibitors as potential chemical/pharmacological probes of SIRT5 and therapeutics for human diseases in which SIRT5 desuccinylase activity is upregulated.
Insights
Researchers developed novel cyclic tripeptides as potent and selective SIRT5 inhibitors. Compound 10 shows significant inhibition and stability, offering a promising lead for developing therapeutics targeting diseases linked to SIRT5 activity.
Area of Science:
- Biochemistry
- Medicinal Chemistry
Background:
- Sirtuins (SIRTs) are a family of NAD+-dependent deacetylases with critical roles in cellular metabolism and disease.
- SIRT5, a key member, is implicated in various pathophysiological conditions, including cancer.
- Developing potent and selective SIRT5 inhibitors is crucial for understanding its biological functions and therapeutic potential.
Purpose of the Study:
- To design and synthesize novel cyclic tripeptides with a unique structural scaffold.
- To identify potent and selective inhibitors of SIRT5 activity.
- To explore new chemical entities for targeting SIRT5-related diseases.
Main Methods:
- Six cyclic tripeptides (8-13) were designed and synthesized using solid-phase peptide synthesis (SPPS).
- Compounds were purified via reversed-phase high-performance liquid chromatography (RP-HPLC) and characterized by high-resolution mass spectrometry (HRMS).
- In vitro assays were employed to evaluate sirtuin inhibition and proteolytic stability.
Main Results:
- Compound 10 demonstrated potent (IC50 ~2.2 μM) and selective inhibition of SIRT5-catalyzed desuccinylation.
- Inhibition was selective, showing at least 60-fold greater potency against SIRT5 compared to SIRT1, SIRT2, SIRT3, and SIRT6.
- Compound 10 exhibited enhanced SIRT5 inhibition and superior proteolytic stability over its linear analog.
Conclusions:
- Compound 10, with its novel scaffold, represents a promising lead compound for developing superior SIRT5 inhibitors.
- This compound can serve as a valuable chemical probe for studying SIRT5.
- It holds potential for therapeutic applications in diseases associated with upregulated SIRT5 desuccinylase activity.
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