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]
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2. [2]
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3. [3]
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4. [4]
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14. [14]
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15. [15]
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16. [16]
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17. [17]
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18. [18]
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19. [19]
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20. [20]
  Guihuang Fang , Ying Liu , Yangyang Feng , Ying Pan , Hongwei Yang , Yongchuan Liu , Maoxiang Wu . Tuning the ion-dipole interactions between fluoro and carbonyl (EC) by electrolyte design for stable lithium metal batteries. Chinese Chemical Letters, 2025, 36(1): 110385-. doi: 10.1016/j.cclet.2024.110385

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