Citation: Hongjin Li, Xiangyan Chen, Minghao Wu, Panpan Song, Xia Zhao. Bicyclic stapled peptides based on p53 as dual inhibitors for the interactions of p53 with MDM2 and MDMX[J]. Chinese Chemical Letters, ;2022, 33(3): 1254-1258. doi: 10.1016/j.cclet.2021.08.130 shu

Bicyclic stapled peptides based on p53 as dual inhibitors for the interactions of p53 with MDM2 and MDMX

Hongjin Li ^{a, b} ,
Xiangyan Chen ^{a, b} ,
Minghao Wu ^{a, b} ,
Panpan Song ^{a, b} ,
Xia Zhao ^{a, b, *,}

a.
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
b.
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China

zhaoxia@ouc.edu.cn

1184748799@qq.com

Received Date: 27 July 2021
Revised Date: 24 August 2021
Accepted Date: 31 August 2021
Available Online: 24 October 2021

Figures(7)

In recent years, the strategy of inhibiting the interactions of p53 with murine double minute 2 (MDM2) and murine double minute X (MDMX) has been proved to be a promising approach for tumor therapy. However, the poor proteolytical stability and low intracellular delivery efficiency of peptide inhibitors limit their clinical application. Here, we designed and synthesized the bicyclic stapled peptides based on p53 by combining all-hydrocarbon stapling and lactam stapling strategies. We demonstrated that bicyclic stapled peptide p53-16 significantly improved α-helicity and proteolytic stability. Especially, p53-16 showed nanomolar binding affinity for MDM2 and MDMX. In addition, p53-16 could penetrate the cell membrane, and selectively inhibited the activity of tumor cells via activating p53 pathway in vitro. Our data suggest that p53-16 is a potential dual inhibitor of MDM2 and MDMX interactions. The bicyclic stapling strategy is a promising drug design strategy for protein–protein interactions inhibitors.
- p53,
- MDM2,
- MDMX,
- All-hydrocarbon stapling strategy,
- Lactam stapling strategy,
- Bicyclic stapling strategy
1. [1]
  R.L. Siegel, K.D. Miller, H.E. Fuchs, CA Cancer J. Clin.71 (2021) 7-33. doi: 10.3322/caac.21654
2. [2]
  P. Chene, Nat. Rev. Cancer 3 (2003) 102-109. doi: 10.1038/nrc991
3. [3]
  A.C. Joerger, A.R. Fersht, Annu. Rev. Biochem. 85 (2016) 375-404. doi: 10.1146/annurev-biochem-060815-014710
4. [4]
  A. Gupta, K. Shah, M.J. Oza, et al., Biomed. Pharmacother. 109 (2019) 484-492. doi: 10.1016/j.biopha.2018.10.155
5. [5]
  K.M. ElSawy, D.P. Lane, C.S. Verma, et al., J. Phys. Chem. B 120 (2016) 320-328. doi: 10.1021/acs.jpcb.5b11162
6. [6]
  N. Rasafar, A. Barzegar, E. M. Aghdam, Life Sci. 245 (2020) 117358. doi: 10.1016/j.lfs.2020.117358
7. [7]
  M.L. Heltberg, S.H. Chen, A. Jimenez, et al., Cell Syst. 9 (2019) 548-558. e545. doi: 10.1016/j.cels.2019.10.010
8. [8]
  O. Karni-Schmidt, M. Lokshin, C. Prives, Annu. Rev. Pathol. Mech. Dis. 11 (2016) 617-644. doi: 10.1146/annurev-pathol-012414-040349
9. [9]
  L. Qin, F. Yang, C. Zhou, et al., J. Am. Chem. Soc. 136 (2014) 18023-18033. doi: 10.1021/ja509223m
10. [10]
  B. Graves, T. Thompson, M. Xia, et al., Proc. Natl. Acad. Sci. U. S. A. 109 (2012) 11788-11793. doi: 10.1073/pnas.1203789109
11. [11]
  J. Soares, L. Raimundo, N.A. Pereira, et al., Pharmacol. Res. 95-96 (2015) 42-52. doi: 10.1016/j.phrs.2015.03.006
12. [12]
  A. Twarda-Clapa, S. Krzanik, K. Kubica, et al., J. Med. Chem. 60 (2017) 4234-4244. doi: 10.1021/acs.jmedchem.7b00104
13. [13]
  S. Kannan, P.G.A. Aronica, Y.S. Tan, et al., ACS Omega. 4 (2019) 5335-5344. doi: 10.1021/acsomega.9b00097
14. [14]
  L. Gao, Z. Yu, D. Meng, et al., Protein Pept. Lett. 22 (2015) 762-766. doi: 10.2174/0929866522666150622101944
15. [15]
  K. Li, C.J. Liu, X.Z. Zhang, Adv. Drug Deliv. Rev. 160 (2020) 36-51. doi: 10.1016/j.addr.2020.10.009
16. [16]
  L. Gao, M. Uttamchandani, S.Q. Yao, Chem. Commun. (Camb. )48 (2012) 2240-2242. doi: 10.1039/c2cc17701c
17. [17]
  A.M. Ali, J. Atmaj, N. Van Oosterwijk, et al., Comput. Struct. Biotechnol. J. 17 (2019) 263-281. doi: 10.1016/j.csbj.2019.01.012
18. [18]
  Y.S. Ong, L. Gao, K.A. Kalesh, et al., Curr. Top. Med. Chem. 17 (2017) 2302-2318.
19. [19]
  J.E. Jee, J. Lim, Y.S. Ong, et al., Org. Biomol. Chem. 14 (2016) 6833-6839. doi: 10.1039/C6OB01104G
20. [20]
  X. Chen, L. Tai, J. Gao, et al., J. Control Release 218 (2015) 29-35. doi: 10.1016/j.jconrel.2015.09.061
21. [21]
  G. Philippe, Y.H. Huang, O. Cheneval, et al., Biopolymers 106 (2016) 853-863. doi: 10.1002/bip.22893
22. [22]
  X. Li, W.D. Tolbert, H.G. Hu, et al., Chem. Sci. 10 (2019) 1522-1530. doi: 10.1039/c8sc03275k
23. [23]
  X. Li, Y. Zou, H.G. Hu, Chin. Chem. Lett. 29 (2018) 1088-1092. doi: 10.1016/j.cclet.2018.01.018
24. [24]
  Y.S. Chang, B. Graves, V. Guerlavais, et al., Proc. Natl. Acad. Sci. U. S. A. 110 (2013) E3445-E3454. doi: 10.1073/pnas.1303002110
25. [25]
  Y. Wu, Y. Zou, L. Sun, et al., Chin. Chem. Lett. 32 (2021) 4045–4048. doi: 10.3390/ijerph18084045
26. [26]
  P.G. Dougherty, J. Wen, X. Pan, et al., J. Med. Chem. 62 (2019) 10098-10107. doi: 10.1021/acs.jmedchem.9b00456
27. [27]
  H.N. Hoang, R.W. Driver, R.L. Beyer, et al., Angew. Chem. Int. Ed. Engl. 55 (2016) 8275-8279. doi: 10.1002/anie.201602079
28. [28]
  S. Ahangarzadeh, M.M. Kanafi, S. Hosseinzadeh, et al., Drug Discov. Today 24 (2019) 1311-1319. doi: 10.1016/j.drudis.2019.05.008
29. [29]
  C. Li, M. Pazgier, C. Li, et al., J. Mol. Biol. 398 (2010) 200-213. doi: 10.1016/j.jmb.2010.03.005
30. [30]
  J. Mu, X. Xie, S. Xiong, et al., Chin. Chem. Lett. 32 (2021) 1897-1901. doi: 10.1016/j.cclet.2021.01.033
31. [31]
  M. Wu, Q. Chen, Y. Wang, et al., Chin. Chem. Lett. 31 (2020) 1288-1292. doi: 10.1016/j.cclet.2019.10.013
32. [32]
  D. Aline, J. Lim, K.C. Wu, et al., J. Med. Chem. 61 (2018) 2962-2972. doi: 10.1021/acs.jmedchem.8b00010
33. [33]
  C. Toniolo, A. Polese, F. Formaggio, et al., J. Am. Chem. Soc. 118 (1996) 2744-2745. doi: 10.1021/ja9537383
34. [34]
  A.D. de Araujo, H.N. Hoang, W.M. Kok, et al., Angew. Chem. Int. Ed. Engl., 53 (2014) 6965-6969. doi: 10.1002/anie.201310245
35. [35]
  W.J. Jeong, M.S. Lee, Y.B. Lim, et al., Biomacromolecules 14 (2013) 2684-2689. doi: 10.1021/bm400532y
36. [36]
  G.J. Hilinski, Y.W. Kim, J. Hong, et al., J. Am. Chem. Soc. 136 (2014) 12314-12322. doi: 10.1021/ja505141j
37. [37]
  Y. Chen, J. Liang, T. Li, et al., Chin. Chem. Lett. 30 (2019) 924-928. doi: 10.3390/genes10110924
38. [38]
  S. Li, X. Zhang, C. Guo, et al., Chem. Commun. (Camb. ) 56 (2020) 15655-15658. doi: 10.1039/d0cc06312f
39. [39]
  K. Sakagami, T. Masuda, K. Kawano, et al., Mol. Pharm. 15 (2018) 1332-1340. doi: 10.1021/acs.molpharmaceut.7b01130
40. [40]
  G.J. Philippe, A. Mittermeier, N. Lawrence, et al., ACS Chem. Biol. 16 (2021) 414-428. doi: 10.1021/acschembio.0c00988
41. [41]
  M. Pazgier, M. Liu, G. Zou, et al., Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 4665. doi: 10.1073/pnas.0900947106
1. [1]
  Yu-Yu Tan , Lin-Heng He , Wei-Min He . Copper-mediated assembly of SO₂F group via radical fluorine-atom transfer strategy. Chinese Chemical Letters, 2024, 35(9): 109986-. doi: 10.1016/j.cclet.2024.109986
2. [2]
  Shuheng Zhang , Yuanyuan Zhang , Wanyu Wang , Yuzhu Hu , Xinchuan Chen , Bilan Wang , Xiang Gao . A combination strategy of DOX and VEGFR-2 targeted inhibitor based on nanomicelle for enhancing lymphoma therapy. Chinese Chemical Letters, 2024, 35(12): 109658-. doi: 10.1016/j.cclet.2024.109658
3. [3]
  Jie Ma , Jianxiang Wang , Jianhua Yuan , Xiao Liu , Yun Yang , Fei Yu . The regulating strategy of hierarchical structure and acidity in zeolites and application of gas adsorption: A review. Chinese Chemical Letters, 2024, 35(11): 109693-. doi: 10.1016/j.cclet.2024.109693
4. [4]
  Shaoqing Du , Xinyong Liu , Xueping Hu , Peng Zhan . Targeting novel sites represents an effective strategy for combating drug resistance. Chinese Chemical Letters, 2025, 36(1): 110378-. doi: 10.1016/j.cclet.2024.110378
5. [5]
  Maosen Xu , Pengfei Zhu , Qinghong Cai , Meichun Bu , Chenghua Zhang , Hong Wu , Youzhou He , Min Fu , Siqi Li , Xingyan Liu . In-situ fabrication of TiO₂/NH₂−MIL-125(Ti) via MOF-driven strategy to promote efficient interfacial effects for enhancing photocatalytic NO removal activity. Chinese Chemical Letters, 2024, 35(10): 109524-. doi: 10.1016/j.cclet.2024.109524
6. [6]
  Dong Cheng , Youyou Feng , Bingxi Feng , Ke Wang , Guoxin Song , Gen Wang , Xiaoli Cheng , Yonghui Deng , Jing Wei . Polyphenol-mediated interfacial deposition strategy for supported manganese oxide catalysts with excellent pollutant degradation performance. Chinese Chemical Letters, 2024, 35(5): 108623-. doi: 10.1016/j.cclet.2023.108623
7. [7]
  Junhua Wang , Xin Lian , Xichuan Cao , Qiao Zhao , Baiyan Li , Xian-He Bu . Dual polarization strategy to enhance CH₄ uptake in covalent organic frameworks for coal-bed methane purification. Chinese Chemical Letters, 2024, 35(8): 109180-. doi: 10.1016/j.cclet.2023.109180
8. [8]
  Wenyu Gao , Liming Zhang , Chuang Zhao , Lixiang Liu , Xingran Yang , Jinbo Zhao . Controlled semi-Pinacol rearrangement on a strained ring: Efficient access to multi-substituted cyclopropanes by group migration strategy. Chinese Chemical Letters, 2024, 35(9): 109447-. doi: 10.1016/j.cclet.2023.109447
9. [9]
  Zheng Zhao , Ben Zhong Tang . An efficient strategy enabling solution processable thermally activated delayed fluorescence emitter with high horizontal dipole orientation. Chinese Journal of Structural Chemistry, 2024, 43(6): 100270-100270. doi: 10.1016/j.cjsc.2024.100270
10. [10]
  A-Yang Wang , Sheng-Hua Zhou , Mao-Yin Ran , Xin-Tao Wu , Hua Lin , Qi-Long Zhu . Regulating the key performance parameters for Hg-based IR NLO chalcogenides via bandgap engineering strategy. Chinese Chemical Letters, 2024, 35(10): 109377-. doi: 10.1016/j.cclet.2023.109377
11. [11]
  Liping Zhao , Xixi Guo , Zhimeng Zhang , Xi Lu , Qingxuan Zeng , Tianyun Fan , Xintong Zhang , Fenbei Chen , Mengyi Xu , Min Yuan , Zhenjun Li , Jiandong Jiang , Jing Pang , Xuefu You , Yanxiang Wang , Danqing Song . Novel berberine derivatives as adjuvants in the battle against Acinetobacter baumannii: A promising strategy for combating multi-drug resistance. Chinese Chemical Letters, 2024, 35(10): 109506-. doi: 10.1016/j.cclet.2024.109506
12. [12]
  Ruixin Liu , Feng Shi , Yanping Xia , Haibing Zhu , Jiawen Cao , Kai Peng , Chuanli Ren , Juan Li , Zhanjun Yang . Universal MOF nanozyme-induced catalytic amplification strategy for label-free electrochemical immunoassay. Chinese Chemical Letters, 2024, 35(11): 109664-. doi: 10.1016/j.cclet.2024.109664
13. [13]
  Zhendong Liu , Sainan Liu , Bin Liu , Qi Meng , Meng Yuan , Chunzheng Yang , Yulong Bian , Ping'an Ma , Jun Lin . Fe(Ⅲ)-juglone nanoscale coordination polymers for cascade chemodynamic therapy through synergistic ferroptosis and apoptosis strategy. Chinese Chemical Letters, 2024, 35(11): 109626-. doi: 10.1016/j.cclet.2024.109626
14. [14]
  Qiang Wu , Baofeng Wang . Exploring synthetic strategy for stabilizing nickel-rich layered oxide cathodes through structural design. Chinese Chemical Letters, 2024, 35(12): 110089-. doi: 10.1016/j.cclet.2024.110089
15. [15]
  Yu-Qi Cao , Ying-Jie Lu , Li Zhang , Jing Zhang , Yin-Long Guo . Vacuum promoted on-tissue derivatization strategy: Unravelling spatial distribution of glycerides on tissue. Chinese Chemical Letters, 2024, 35(12): 109788-. doi: 10.1016/j.cclet.2024.109788
16. [16]
  Yanting Yang , Guorong Wang , Kangjing Li , Wen Yang , Jing Zhang , Jian Zhang , Shili Li , Xianming Zhang . Tuning up of chromism, luminescence in cadmium-viologen complexes through polymorphism strategy: Inkless erasable printing application. Chinese Chemical Letters, 2025, 36(1): 110123-. doi: 10.1016/j.cclet.2024.110123
17. [17]
  Gaojian Yang , Zhiyang Li , Rabia Usman , Zhu Chen , Yuan Liu , Song Li , Hui Chen , Yan Deng , Yile Fang , Nongyue He . DNA walker induced "signal on" fluorescence aptasensor strategy for rapid and sensitive detection of extracellular vesicles in gastric cancer. Chinese Chemical Letters, 2025, 36(2): 109930-. doi: 10.1016/j.cclet.2024.109930
18. [18]
  Xilin Bai , Wei Deng , Jingjuan Wang , Ming Zhou . Enrichment-enhanced detection strategy in the optimized monitoring system of dopamine with carbon dots-based probe. Chinese Chemical Letters, 2025, 36(2): 109959-. doi: 10.1016/j.cclet.2024.109959
19. [19]
  Chuyuan Lin , Hui Lin , Lingxing Zeng . Optimization strategy for rechargeable Zn metal batteries over wide-pH aqueous electrolytes. Chinese Journal of Structural Chemistry, 2025, 44(1): 100407-100407. doi: 10.1016/j.cjsc.2024.100407
20. [20]
  Linjie Ju , Zhongxi Huang , Qian Shen , Chan Fu , Shuanghe Li , Wenjie Duan , Chenfeng Xu , Weizhen An , Zhiqiang Zhai , Jifu Wei , Changmin Yu , Guoren Zhou . Glutathione depletion based Pt(Ⅳ) hybrid mesoporous organosilica delivery system to conquer cisplatin chemoresistance: A “one stone three birds” strategy. Chinese Chemical Letters, 2024, 35(10): 109450-. doi: 10.1016/j.cclet.2023.109450

Get Citation

PDF

XML

Metrics

PDF Downloads(8)
Abstract views(564)
HTML views(76)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142