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]
  Chen Zhuo , Xu Yufang , Qian Xuhong . Naphthalimides and analogues as antitumor agents: A review on molecular design, bioactivity and mechanism of action. Chinese Chemical Letters, 2018, 29(12): 1741-1756. doi: 10.1016/j.cclet.2018.09.020
2. [2]
  Li Xiang , Zou Yan , Hu Hong-Gang . Different stapling-based peptide drug design: Mimicking α-helix as inhibitors of protein-protein interaction. Chinese Chemical Letters, 2018, 29(7): 1088-1092. doi: 10.1016/j.cclet.2018.01.018
3. [3]
  Kun Fang , Guo-Qiang Dong , Hai Gong , Na Liu , Zhen-Gang Li , Shi-Ping Zhu , Zhen-Yuan Miao , Jian-Zhong Yao , Wan-Nian Zhang , Chun-Quan Sheng . Design, synthesis and biological evaluation of E-ring modifi ed evodiamine derivatives as novel antitumor agents. Chinese Chemical Letters, 2014, 25(7): 978-982. doi: 10.1016/j.cclet.2014.03.043
4. [4]
  Hacer Karatas , Shirley Y. Lee , Elizabeth C. Townsend , Fang Cao , Jing Xu , Denzil Bernard , Liu Liu , Yali Dou , Shaomeng Wang . Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein-protein interaction as inhibitors of the MLL1 methyltransferase activity. Chinese Chemical Letters, 2015, 26(4): 455-458. doi: 10.1016/j.cclet.2015.03.030
5. [5]
  Lei ZHANG , Zhuo CHEN . Research Progress of Structure Based Antitumor Drug Design. Chinese Journal of Structural Chemistry, 2020, 39(12): 2085-2090. doi: 10.14102/j.cnki.0254–5861.2011–3036
6. [6]
  Yu Fei SONG , Pin YANG , Leung SHEH . Synthesis of Some Novel 2,6-Dimethoxyhydroquinone-3-mercaptoacetyl-peptide Conjugates as Potential Antitumor Agents. Chinese Chemical Letters, 2000, 11(8): 667-670.
7. [7]
  Wen-Ya Wang , Cheng-Wu Shen , Zhi-Jie Weng , Tie-Chuang Wang , Chuang Zhang , Xun-Qi Jin , Jian-Qi Li . Design, synthesis and biological evaluation of novel dicarbonylalkyl piperazine derivatives as neuroprotective agents. Chinese Chemical Letters, 2016, 27(03): 387-390. doi: 10.1016/j.cclet.2015.11.002
8. [8]
  Xu Yuan-Yuan , Qian An-Ran , Cao Xu-Feng , Ling Chen-Yu , Cao Yong-Bing , Wang Rui-Lian , Li Yi-Su , Yang Yu-She . Design and synthesis of novel triazole derivatives containing γ-lactam as potential antifungal agents. Chinese Chemical Letters, 2016, 27(5): 703-706. doi: 10.1016/j.cclet.2016.01.040
9. [9]
  Hua Wang , Qi Dong You , Zhi Yu Li , Yi Quan Zou . Design, synthesis and antitumor activity of 3-substituted quinolone derivatives (Ⅰ). Chinese Chemical Letters, 2008, 19(12): 1395-1397. doi: 10.1016/j.cclet.2008.09.034
10. [10]
  Zhonghua Li , Haibin Qu , Lan Fang , Songgu Wu , Junbo Gong . A new strategy to design isostructural salts: The case of the antitumor drug dimethylaminomicheliolide. Chinese Chemical Letters, 2023, 34(2): 107504-1-107504-4. doi: 10.1016/j.cclet.2022.05.018
11. [11]
  Ying Wen , Ning Jing , Fangjun Huo , Caixia Yin . Rational design of a turn-on fluorescent probe for visualization of GRP78 protein in tumor models. Chinese Chemical Letters, 2023, 34(3): 107604-1-107604-4. doi: 10.1016/j.cclet.2022.06.027
12. [12]
  Xiu-Jun Wang , Ming-Li Yang , Lan-Ping Zhang , Tong Yao , Cheng Chen , Lian-Gang Mao , Yin Wang , Jie Wu . Design of novel bis-benzimidazole derivatives as DNA minor groove binding agents. Chinese Chemical Letters, 2014, 25(4): 589-592. doi: 10.1016/j.cclet.2014.01.019
13. [13]
  Sunil Vodela , Raghu Vardhan Reddy Mekala , Ravinder Reddy Danda , Venkateshwarlu Kodhati . Design, synthesis and screening of some novel benzoxazole based 1, 3, 4-oxadiazoles as potential antimicrobial agents. Chinese Chemical Letters, 2013, 24(07): 625-628.
14. [14]
  Hui Tang , Juan Wu , Wen Zhang , Lei Zhao , Ya-Hui Zhang , Cheng-Wu Shen . Design, synthesis and biological evaluation of novel non-azole derivatives as potential antifungal agents. Chinese Chemical Letters, 2015, 26(9): 1161-1164. doi: 10.1016/j.cclet.2015.04.030
15. [15]
  Xue Hui Zhang , Hong Yu , Wu Zhong , Li Li Wang , Song Li . Structure-based design, synthesis of novel inhibitors of Mycobacterium tuberculosis FabH as potential anti-tuberculosis agents. Chinese Chemical Letters, 2009, 20(9): 1019-1022. doi: 10.1016/j.cclet.2009.04.018
16. [16]
  Chen Wenhua , Yao Xue , Huang Zhenghui , Mao Fei , Guan Longfei , Tang Yun , Jiang Hualiang , Li Jian , Huang Jin , Jiang Lubin , Zhu Jin . Novel dual inhibitors against FP-2 and PfDHFR as potential antimalarial agents: Design, synthesis and biological evaluation. Chinese Chemical Letters, 2019, 30(1): 250-254. doi: 10.1016/j.cclet.2017.11.041
17. [17]
  Chen Wei , Li Yuxin , Zhou Yunyun , Ma Yi , Li Zhengming . Design, synthesis and SAR study of novel sulfonylurea derivatives containing arylpyrimidine moieties as potential anti-phytopathogenic fungal agents. Chinese Chemical Letters, 2019, 30(12): 2160-2162. doi: 10.1016/j.cclet.2019.04.072
18. [18]
  Dai Qiuzi , Chen Jiwei , Gao Chunmei , Qinsheng Sun , Yuan Zigao , Yuyang Jiang . Design, synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents. Chinese Chemical Letters, 2020, 31(2): 404-408. doi: 10.1016/j.cclet.2019.06.019
19. [19]
  Jin Yi Xu , Qian Ran , Wei Yi Hua , Xiao Ming Wu , Qiu Juan Wang , Jing Zhang . Design and synthesis of 2-alkylbenzimidazole derivatives as novel non-peptide angiotensin Ⅱ AT₁ receptor antagonists. Chinese Chemical Letters, 2007, 18(3): 251-254. doi: 10.1016/j.cclet.2006.12.029

Get Citation

PDF

XML

Metrics

PDF Downloads(2)
Abstract views(125)
HTML views(14)

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