Citation: Jinghui Zhang, Huixin Xu, Baishi Wang, Xuekai Zhang, Lei Fu, Yannan Li, Guanzhao Wu, Zitong Zhao, Lu Liu, Ting Yang, Zheyu Zhang, Jinbo Yang, Tao Jiang, Peiju Qiu, Rilei Yu. In silico design of anti-tumor mini-protein targeting MDM2[J]. Chinese Chemical Letters, ;2023, 34(5): 107871. doi: 10.1016/j.cclet.2022.107871 shu

In silico design of anti-tumor mini-protein targeting MDM2

Jinghui Zhang ^{a, b, c, 1} ,
Huixin Xu ^{a, b, c, 1} ,
Baishi Wang ^{a, 1} ,
Xuekai Zhang ^{d, 1} ,
Lei Fu ^a ,
Yannan Li ^a ,
Guanzhao Wu ^a ,
Zitong Zhao ^a ,
Lu Liu ^a ,
Ting Yang ^a ,
Zheyu Zhang ^a ,
Jinbo Yang ^{a, c} ,
Tao Jiang ^{a, b} ,
Peiju Qiu ^{a, c, *,} ,
Rilei Yu ^{a, b, c, *,}

a.
Key Laboratory of Marine Drugs, Chinese 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
c.
Innovation Center for Marine Drug Screening & Evaluation Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266003, China
d.
Department of Biological Engineering, College of Chemical and Biological Engineering, Shandong University of Science and Technology, Qingdao 266590, China

peijuqiu@ouc.edu.cn

ryu@ouc.edu.cn

Received Date: 5 April 2022
Revised Date: 27 September 2022
Accepted Date: 29 September 2022
Available Online: 13 October 2022

Figures(4)

We designed a disulfide-crosslinked mini-protein with a two-helical topology consisting of L- and D-amino acids, which was exceptionally stable in serum. Therefore, we further used it as a scaffold to design mini-proteins targeting p53 positive tumor cells. Based on bifunctional grafting, key residues from the transactivation domain of p53 and a designed unnatural amino acid were grafted into the helix constituted by L-amino acids to confer the mini-protein with MDM2 inhibitory activity. Meanwhile, ten Arg residues were introduced to improve its membrane penetrating capacity. Among the mini-proteins, UPROL-10e showed nano-molar binding affinity on MDM2 and cellular toxicity on p53 expressing HCT116 cells.
- Protein design,
- Antitumor agents,
- In silico design,
- Constrained peptide,
- Epitope grafting
1. [1]
  G. Bhardwaj, V.K. Mulligan, C.D. Bahl, et al., Nature 538 (2016) 329–335. doi: 10.1038/nature19791
2. [2]
  P. Chene, Nat. Rev. Cancer 3 (2003) 102–109. doi: 10.1038/nrc991
3. [3]
  J.C. Marine, M.A. Dyer, A.G. Jochemsen, J. Cell Sci. 120 (2007) 371–378. doi: 10.1242/jcs.03362
4. [4]
  K.H. Vousden, D.P. Lane, Nat. Rev. Mol. Cell Biol. 8 (2007) 275–283. doi: 10.1038/nrm2147
5. [5]
  Z. Han, Y. Li, S. Roelle, et al., Bioconjug. Chem. 28 (2017) 1031–1040. doi: 10.1021/acs.bioconjchem.6b00719
6. [6]
  C. Li, M. Liu, J. Monbo, et al., J. Am. Chem. Soc. 130 (2008) 13546–13548. doi: 10.1021/ja8042036
7. [7]
  Y. Ji, S. Majumder, M. Millard, et al., J. Am. Chem. Soc. 135 (2013) 11623–11633. doi: 10.1021/ja405108p
8. [8]
  C. Li, M. Pazgier, M. Liu, W.Y. Lu, W. Lu, Angew. Chem. Int. Ed. 48 (2009) 8712–8715. doi: 10.1002/anie.200904550
9. [9]
  C.E. Laplaza, R.H. Holm, J. Am. Chem. Soc. 123 (2001) 10255–10264.
10. [10]
  S.M. Fuchs, R.T. Raines, Biochemistry 43 (2004) 2438–2444.
11. [11]
  D. Fujiwara, H. Kitada, M. Oguri, et al., Angew. Chem. Int. Ed. 55 (2016) 10612–10615. doi: 10.1002/anie.201603230
12. [12]
  M. Pazgier, M. Liu, G. Zou, et al., Proc. Natl. Acad. Sci. U. S. A. 106 (2009) 4665–4670. doi: 10.1073/pnas.0900947106
13. [13]
  M. Liu, M. Pazgier, C. Li, et al., Angew. Chem. Int. Ed. 49 (2010) 3649–3652. doi: 10.1002/anie.201000329
1. [1]
  Jin Wang , Xiaoyan Pan , Junyu Zhang , Qingqing Zhang , Yanchen Li , Weiwei Guo , Jie Zhang . Active molecule-based theranostic agents for tumor vasculature normalization and antitumor efficacy. Chinese Chemical Letters, 2024, 35(8): 109187-. doi: 10.1016/j.cclet.2023.109187
2. [2]
  Bharathi Natarajan , Palanisamy Kannan , Longhua Guo . Metallic nanoparticles for visual sensing: Design, mechanism, and application. Chinese Journal of Structural Chemistry, 2024, 43(9): 100349-100349. doi: 10.1016/j.cjsc.2024.100349
3. [3]
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4. [4]
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5. [5]
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6. [6]
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7. [7]
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8. [8]
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9. [9]
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10. [10]
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11. [11]
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12. [12]
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13. [13]
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14. [14]
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15. [15]
  Jiajun Wang , Guolin Yi , Shengling Guo , Jianing Wang , Shujuan Li , Ke Xu , Weiyi Wang , Shulai Lei . Computational design of bimetallic TM₂@g-C₉N₄ electrocatalysts for enhanced CO reduction toward C₂ products. Chinese Chemical Letters, 2024, 35(7): 109050-. doi: 10.1016/j.cclet.2023.109050
16. [16]
  Xin Dong , Tianqi Chen , Jing Liang , Lei Wang , Huajie Wu , Zhijin Xu , Junhua Luo , Li-Na Li . Structure design of lead-free chiral-polar perovskites for sensitive self-powered X-ray detection. Chinese Journal of Structural Chemistry, 2024, 43(6): 100256-100256. doi: 10.1016/j.cjsc.2024.100256
17. [17]
  Yuting Wu , Haifeng Lv , Xiaojun Wu . Design of two-dimensional porous covalent organic framework semiconductors for visible-light-driven overall water splitting: A theoretical perspective. Chinese Journal of Structural Chemistry, 2024, 43(11): 100375-100375. doi: 10.1016/j.cjsc.2024.100375
18. [18]
  Wenbi Wu , Yinchu Dong , Haofan Liu , Xuebing Jiang , Li Li , Yi Zhang , Maling Gou . Modification of plasma protein for bioprinting via photopolymerization. Chinese Chemical Letters, 2024, 35(8): 109260-. doi: 10.1016/j.cclet.2023.109260
19. [19]
  Jing Zhang , Charles Wang , Yaoyao Zhang , Haining Xia , Yujuan Wang , Kun Ma , Junfeng Wang . Application of magnetotactic bacteria as engineering microrobots: Higher delivery efficiency of antitumor medicine. Chinese Chemical Letters, 2024, 35(10): 109420-. doi: 10.1016/j.cclet.2023.109420
20. [20]
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