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. 2021 May 19;12(6):1017-1023.
doi: 10.1021/acsmedchemlett.1c00174. eCollection 2021 Jun 10.

Discovery of Novel PTP1B Inhibitors Derived from the BH3 Domain of Proapoptotic Bcl-2 Proteins with Antidiabetic Potency

Chuanliang Zhang  1   2   3 , Lijuan Wu  2   3 , Xiaochun Liu  2   3 , Jiangming Gao  2   3 , Shan Liu  2   3 , Juan Wu  2   3 , Dingmin Huang  1 , Zhenwei Wang  1 , Xianbin Su  1
Affiliations

Discovery of Novel PTP1B Inhibitors Derived from the BH3 Domain of Proapoptotic Bcl-2 Proteins with Antidiabetic Potency

Chuanliang Zhang et al. ACS Med Chem Lett. .

Abstract

BH3 peptide analogues are generally believed to exhibit great potency as cancer therapeutics via targeting antiapoptotic Bcl-2 proteins. Here, we describe the synthesis and identification of a new class of palmitoylated peptide BH3 analogues derived from the core region (h1-h4) of BH3 domains of proapoptotic Bcl-2 proteins and as alternative PTP1B inhibitors with antidiabetic potency in vitro and in vivo. PTP1B inhibitors are attractive for treatment of type 2 diabetes. We design the analogues using a simple lipidation approach and discovered novel lead analogues with promising antidiabetic potency in vitro and in vivo. The results presented here expanded the alternative target and function for the BH3 peptide analogues from one member Bim to other members of the proapoptotic Bcl-2 proteins and emphasize their therapeutic potential in T2DM. Furthermore, our findings may provide new proof of the regulatory function of Bcl-2 family proteins in mitochondrial nutrient and energy metabolism.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Peptide analogues of the BH3 domain derived from proapoptotic Bcl-2 proteins via the same lipidation modification with Pal-BimBH3, a Bim-BH3 analogue described in our previous work.
Figure 2
Figure 2
Dose–response curves for PTP1B inhibition of the BH3 analogues.
Figure 3
Figure 3
Far-UV CD spectra of the peptide BH3 analogues in solution (0.5 mg/mL in 50 mM Tris and 100 mM NaCl buffer, 25 °C).
Figure 4
Figure 4
Effect of selected analogues on insulin-stimulated glucose uptake in insulin-resistant HepG2 cells. A glucose uptake assay was performed using the fluorescent d-glucose analogue 2-NBDG. The insulin-resistant HepG2 cells were treated with different concentration analogues or liraglutide for 24 h, and the vehicle group was administered an equivalent volume of dimethyl sulfoxide (DMSO) as a control. Relative fluorescence intensity minus background was used for subsequent statistical analyses. The results shown are mean ± SD (n = 4). *, P < 0.05, **, P < 0.01 when compared with vehicle.
Figure 5
Figure 5
Palmitoylated peptide analogues Pal-BakBH3, Pal-BikBH3, Pal-BidBH3, and Pal-BimBH3 demonstrate blood glucose lowering duration and improvement of glucose tolerance in vivo. (A) After a 1 week intervention, diabetic db/db mice were treated with a single s.c. dose of analogue Pal-BakBH3, Pal-BikBH3, Pal-BidBH3, and Pal-BimBH3, liraglutide, or vehicle followed by a blood glucose monitoring over 12 h on day 8. (B) On day 9, GTT after overnight fast for the indicated peptides, liraglutide, or vehicle (s.c. dosing) followed by glucose (2 g/kg, i.g.) 0.5 h later. (C) Average area under the curve (AUC) values for the GTT data shown in part B. Data are mean ± SD for n = 5 mice per treatment condition. *, P < 0.05, **, P < 0.01 vs vehicle.
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References

    1. Cory S.; Adams J. M. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer 2002, 2 (9), 647–656. 10.1038/nrc883. - DOI - PubMed
    1. Delbridge A. R. D.; Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ. 2015, 22 (7), 1071–1080. 10.1038/cdd.2015.50. - DOI - PMC - PubMed
    1. Checco J. W.; Lee E. F.; Evangelista M.; Sleebs N. J.; Rogers K.; Pettikiriarachchi A.; Kershaw N. J.; Eddinger G. A.; Belair D. G.; Wilson J. L.; Eller C. H.; Raines R. T.; Murphy W. L.; Smith B. J.; Gellman S. H.; Fairlie W. D. α/β-Peptide Foldamers Targeting Intracellular Protein–Protein Interactions with Activity in Living Cells. J. Am. Chem. Soc. 2015, 137 (35), 11365–11375. 10.1021/jacs.5b05896. - DOI - PMC - PubMed
    1. Boersma M. D.; Haase H. S.; Peterson-Kaufman K. J.; Lee E. F.; Clarke O. B.; Colman P. M.; Smith B. J.; Horne W. S.; Fairlie W. D.; Gellman S. H. Evaluation of Diverse α/β-BackbonePatterns for Functional α-Helix Mimicry: Analogues of the Bim BH3 Domain. J. Am. Chem. Soc. 2012, 134 (1), 315–323. 10.1021/ja207148m. - DOI - PMC - PubMed
    1. Sadowsky J. D.; Fairlie W. D.; Hadley E. B.; Lee H.-S.; Umezawa N.; Nikolovska-Coleska Z.; Wang S.; Huang D. C. S.; Tomita Y.; Gellman S. H. (α/β+α)-Peptide Antagonists of BH3 Domain/Bcl-xL Recognition: Toward General Strategies for Foldamer-Based Inhibition of Protein–Protein Interactions. J. Am. Chem. Soc. 2007, 129 (1), 139–154. 10.1021/ja0662523. - DOI - PubMed

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