Citation: ZHOU Lu, JIN Feng, LIU Ying, SHANG Er-Chang, WEI Ping, LI Chun-Mei, LAI Lu-Hua. Isatin Dual Functional Inhibitors: Modulating the Aggregation State and Enzyme Activity of SARS-3CL Proteinase[J]. Acta Physico-Chimica Sinica, ;2012, 28(10): 2418-2422. doi: 10.3866/PKU.WHXB201209143 shu

Isatin Dual Functional Inhibitors: Modulating the Aggregation State and Enzyme Activity of SARS-3CL Proteinase

ZHOU Lu ^1,3 ,
JIN Feng ¹ ,
LIU Ying ^1,2, ,
SHANG Er-Chang ¹ ,
WEI Ping ¹ ,
LI Chun-Mei ¹ ,
LAI Lu-Hua ^1,2,

1.
1 Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Structural Chemistry of Unstable and Stable Species, Institute of Physical Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China;
2 Center for Quantitative Biology, Peking University, Beijing 100871, P. R. China;
3 School of Pharmacy, Fudan University, Shanghai 201203, P. R. China

Received Date: 25 July 2012
Available Online: 14 September 2012
Fund Project: 国家自然科学基金(90913021, 20473001, 11021463) (90913021, 20473001, 11021463)国家重点基础研究发展规划项目(973) (2009CB9185003)资助 (973) (2009CB9185003)

The 1-(2-naphthlmethyl) isatin-5-formamide compounds can inhibit SARS-3CL proteinase by binding to its substrate pocket, while the N-terminal octapeptide of SARS-3CL proteinase was found to act as a dimerization inhibitor. In this work, the dual functional inhibitors which can occupy both substrate pocket of SARS-3CL proteinase and its dimer interface were designed. Six title compounds were tten by linking 1-(2-naphthlmethyl) isatin-5-formic acid and N-terminal octapeptides using a polyglycine linker through solid-phase peptide synthesis method. The in vitro inhibition activity against SARS-3CL proteinase was measured by continuous colorimetric assay using colorimetric substrate. Compound 3 showed the highest inhibition activity with an IC₅₀ (half maximal inhibitory concentration of a substance) of 3.8 μmol·L^-1. The change of inhibition activity with the linker length was studied. Inhibitors with the even spacers were showed better activity than the odd ones, which could be explained by the angle restriction of peptide bonds. The modulating of the aggregation state and enzyme activity towards SARS-3CL proteinase were studied using sedimentation velocity experiments. Compound 3 was found to not only inhibit the enzyme activity of SARS-3CL proteinase, but also shift the monomer-dimer equilibrium of the enzyme. The integrated control result is inhibiting SARS-3CL proteinase dimer formation. This work provides an example of using synthesized compounds to study enzyme activity regulation mechanism.
- Isatin derivative,
- Modulation,
- SARS-3CL proteinase,
- Dimerization,
- Dual functional inhibitor
1. [1]
  
  (1) Bogert, M. T.; Nabenhauer, F. P. J. Am. Chem. Soc. 1924, 46,1702. doi: 10.1021/ja01672a021
2. [2]
  (2) Trinka, P.; Slegel, P.; Reiter, J. J. Prakt. Chem. 1996, 338, 675.doi: 10.1002/(ISSN)1521-3897
3. [3]
  (3) Praveen, C.; Ayyanar, A.; Perumal, P. T. Bioorg. Med. Chem. Lett. 2011, 21, 4072. doi: 10.1016/j.bmcl.2011.04.117
4. [4]
  (4) Shingade, S. G.; Bari, S. B.;Waghmare, U. B. Med. Chem. Res.2012, 21, 1302. doi: 10.1007/s00044-011-9644-y
5. [5]
  (5) Adibi, H.; Khodaei, M.; Pakravan, P.; Abiri, R. Pharm. Chem. J.2010, 44, 219. doi: 10.1007/s11094-010-0436-3
6. [6]
  (6) Pervez, H.; Iqbal, M. S.; Tahir, M. Y.; Nasim, F. U.; Choudhary,M. I.; Khan, K. M. J. Enzym. Inhib. Med. Chem. 2008, 23, 848.doi: 10.1080/14756360701746179
7. [7]
  (7) Pervez, H.; Lqbal, M. S.; Tahir, M. Y.; Choudhary, M. I.; Khan,K. M. Nat. Prod. Res. 2007, 21, 1178. doi: 10.1080/14786410601129770
8. [8]
  (8) Dra vich, P. S.; Prins, T. J.; Zhou, R.;Webber, S. E.;Marakovits, J. T.; Fuhrman, S. A.; Patick, A. K.; Matthews, D.A.; Lee, C. A.; Ford, C. E.; Burke, B. J.; Rejto, P. A.;Hendrickson, T. F.; Brown, E. L.; Meador, J.W.; Ferre, R. A.;Harr, J. E. V.; Kosa, M. B.;Worland, S. T. J. Med. Chem. 1999,42, 1213. doi: 10.1021/jm9805384
9. [9]
  (9) Webber, S. E.; Tikhe, J.;Worland, S. T.; Fuhrman, S. A.;Hendrickson, T. F.; Matthews, D. A.; Love, R. A.; Patick, A. K.;Meador, J.W.; Ferre, R. A.; Brown, E. L.; DeLisle, D. M.; Ford,C. E.; Binford, S. L. J. Med. Chem. 1996, 39, 5072. doi: 10.1021/jm960603e
10. [10]
  (10) Vine, K. L.; Matesic, L.; Locke, J. M.; Ranson, M.; Skropeta, D.Anti-Cancer Agents Med. Chem. 2009, 9, 397.
11. [11]
  (11) Kandile, N. G.; Mohamed, M. I.; Ismaeel, H. M. J. Enzym. Inhib. Med. Chem. 2012, 27, 330. doi: 10.3109/14756366.2011.588950
12. [12]
  (12) Peiris, J. S. M.; Lai, S. T.; Poon, L. L. M.; Guan, Y.; Yam, L. Y.C.; Lim,W.; Nicholls, J.; Yee,W. K. S.; Yan,W.W.; Cheung,M. T. ; Cheng, V. C. C.; Chan, K. H.; Tsang, D. N. C.; Yung, R.W. H.; Ng, T. K.; Yuen, K. Y. Lancet 2003, 361, 1319. doi: 10.1016/S0140-6736(03)13077-2
13. [13]
  (13) Yang, H. T.; Yang, M. J.; Ding, Y.; Liu, Y.W.; Lou, Z. Y.; Zhou,Z.; Sun, L.; Mo, L. J.; Ye, S.; Pang, H.; Gao, G. F.; Anand, K.;Bartlam, M.; Hilgenfeld, R.; Rao, Z. H. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 13190. doi: 10.1073/pnas.1835675100
14. [14]
  (14) Lai, L. H.; Han, X. F.; Chen, H.;Wei, P.; Huang, C. K.; Liu, S.Y.; Fan, K. Q.; Zhou, L.; Liu, Z. M.; Pei, J. F.; Liu, Y. Curr. Pharm. Des. 2006, 12, 4555. doi: 10.2174/138161206779010396
15. [15]
  (15) Chen, L. R.;Wang, Y. C.; Lin, Y.W.; Chou, S. Y.; Chen, S. F.;Liu, L. T.;Wu, Y. T.; Chih-Jung, K. B.; Chen, T. S. S.; Juang, S.H. Bioorg. Med. Chem. Lett. 2005, 15, 3058. doi: 10.1016/j.bmcl.2005.04.027
16. [16]
  (16) Zhou, L.; Liu, Y.; Zhang,W. L.;Wei, P.; Huang, C. K.; Pei, J. F.;Yuan, Y. X.; Lai, L. H. J. Med. Chem. 2006, 49, 3440. doi: 10.1021/jm0602357
17. [17]
  (17) Liu, Y.; Zheng, T. F.; Jin, F.; Zhou, L.; Liu, Z. M.;Wei, P.; Lai,L. H. Acta Chim. Sin. 2007, 65, 1707. [刘莹, 郑腾飞,金凤, 周璐, 刘振明, 魏平, 来鲁华. 化学学报, 2007, 65,1707.]
18. [18]
  (18) Fan, K. Q.;Wei, P.; Feng, Q.; Chen, S. D.; Huang, C. K.; Ma,L.; Lai, B.; Pei, J. F.; Liu, Y.; Chen, J. G.; Lai, L. H. J. Biol. Chem. 2004, 279, 1637. doi: 10.1074/jbc.M310875200
19. [19]
  (19) Chen, H.;Wei, P.; Huang, C. K; Tan, L.; Liu, Y.; Lai, L. H.J. Biol. Chem. 2006, 281, 13894. doi: 10.1074/jbc.M510745200
20. [20]
  (20) Wei, P.; Fan, K. Q.; Chen, H.; Ma, L.; Huang, C. K.; Tan, L.; Xi,D.; Li, C. M.; Liu, Y.; Cao, A. N.; Lai, L. H. Biochem. Biophys. Res. Commun. 2006, 339, 865. doi: 10.1016/j.bbrc.2005.11.102
21. [21]
  (21) Wei, P.; Li, C. M.; Zhou, L.; Liu, Y.; Lai, L. H. Acta Phys. -Chim. Sin. 2010, 26, 1093. [魏平, 李春梅, 周璐, 刘莹, 来鲁华. 物理化学学报, 2010, 26, 1093.] doi: 10.3866/PKU.WHXB20100449
22. [22]
  (22) Li, C. M.; Qi, Y. F.; Teng, X.; Yang, Z. C.;Wei, P.; Zhang, C. S.;Tan, L.; Zhou, L.; Liu, Y.; Lai, L. H. J. Biol. Chem. 2010, 285,28134. doi: 10.1074/jbc.M109.095851
23. [23]
  (23) Fan, K. Q.; Ma, L.; Han, X. F.; Liang, H. H.;Wei, P.; Liu, Y.;Lai, L. H. Biochem. Biophys. Res. Commun. 2005, 329, 934.doi: 10.1016/j.bbrc.2005.02.061
24. [24]
  (24) Yang, H. T.; Xie,W. Q.; Xue, X. Y.; Yang, K. L.; Ma, J.; Liang,W. X.; Zhao, Q.; Zhou, Z.; Pei, D. Q.; Ziebuhr, J.; Hilgenfeld,R.; Yuen, K. Y.;Wong, L.; Gao, G. X.; Chen, S. J.; Chen, Z.;Ma, D.W.; Bartlam, M.; Rao, Z. H. PLoS Biol. 2005, 3, 1742.
25. [25]
  (25) Huang, C. K.;Wei, P.; Fan, K. Q.; Liu, Y.; Lai, L. H.Biochemistry 2004, 43, 4568. doi: 10.1021/bi036022q
1. [1]
  Yihui Song , Shangshang Qin , Kai Wu , Chengyun Jin , Bin Yu . 生物化学在高水平创新型药学人才培养中的交叉融合应用——以去甲基化酶LSD1抑制剂的活性评价为例. University Chemistry, 2025, 40(6): 341-352. doi: 10.12461/PKU.DXHX202406018
2. [2]
  Jianfeng Yan , Yating Xiao , Xin Zuo , Caixia Lin , Yaofeng Yuan . Comprehensive Chemistry Experimental Design of Ferrocenylphenyl Derivatives. University Chemistry, 2024, 39(4): 329-337. doi: 10.3866/PKU.DXHX202310005
3. [3]
  Xiaofei Liu , He Wang , Li Tao , Weimin Ren , Xiaobing Lu , Wenzhen Zhang . Electrocarboxylation of Benzylic Phosphates and Phosphinates with Carbon Dioxide. Acta Physico-Chimica Sinica, 2024, 40(9): 2307008-0. doi: 10.3866/PKU.WHXB202307008
4. [4]
  Yonghui ZHOU , Rujun HUANG , Dongchao YAO , Aiwei ZHANG , Yuhang SUN , Zhujun CHEN , Baisong ZHU , Youxuan ZHENG . Synthesis and photoelectric properties of fluorescence materials with electron donor-acceptor structures based on quinoxaline and pyridinopyrazine, carbazole, and diphenylamine derivatives. Chinese Journal of Inorganic Chemistry, 2024, 40(4): 701-712. doi: 10.11862/CJIC.20230373
5. [5]
  Yikai Wang , Xiaolin Jiang , Haoming Song , Nan Wei , Yifan Wang , Xinjun Xu , Cuihong Li , Hao Lu , Yahui Liu , Zhishan Bo . Thickness-Insensitive, Cyano-Modified Perylene Diimide Derivative as a Cathode Interlayer Material for High-Efficiency Organic Solar Cells. Acta Physico-Chimica Sinica, 2025, 41(3): 2406007-0. doi: 10.3866/PKU.WHXB202406007
6. [6]
  Chunling Qin , Shuang Chen , Hassanien Gomaa , Mohamed A. Shenashen , Sherif A. El-Safty , Qian Liu , Cuihua An , Xijun Liu , Qibo Deng , Ning Hu . Regulating HER and OER Performances of 2D Materials by the External Physical Fields. Acta Physico-Chimica Sinica, 2024, 40(9): 2307059-0. doi: 10.3866/PKU.WHXB202307059
7. [7]
  Shasha SUN , Weichun HUANG , Mengke WANG . Research progress of interface regulation strategies and applications of two‑dimensional MXenes. Chinese Journal of Inorganic Chemistry, 2025, 41(8): 1465-1482. doi: 10.11862/CJIC.20240430
8. [8]
  Min LIU , Huapeng RUAN , Zhongtao FENG , Xue DONG , Haiyan CUI , Xinping WANG . Neutral boron-containing radical dimers. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 123-130. doi: 10.11862/CJIC.20240362
9. [9]
  Zhongyan Cao , Shengnan Jin , Yuxia Wang , Yiyi Chen , Xianqiang Kong , Yuanqing Xu . Advances in Highly Selective Reactions Involving Phenol Derivatives as Aryl Radical Precursors. University Chemistry, 2025, 40(4): 245-252. doi: 10.12461/PKU.DXHX202405186
10. [10]
  Qingjun PAN , Zhongliang GONG , Yuwu ZHONG . Advances in modulation of the excited states of photofunctional iron complexes. Chinese Journal of Inorganic Chemistry, 2025, 41(1): 45-58. doi: 10.11862/CJIC.20240365
11. [11]
  Weicheng Feng , Jingcheng Yu , Yilan Yang , Yige Guo , Geng Zou , Xiaoju Liu , Zhou Chen , Kun Dong , Yuefeng Song , Guoxiong Wang , Xinhe Bao . Regulating the High Entropy Component of Double Perovskite for High-Temperature Oxygen Evolution Reaction. Acta Physico-Chimica Sinica, 2024, 40(6): 2306013-0. doi: 10.3866/PKU.WHXB202306013
12. [12]
  Weikang Wang , Yadong Wu , Jianjun Zhang , Kai Meng , Jinhe Li , Lele Wang , Qinqin Liu . Green H₂O₂ synthesis via melamine-foam supported S-scheme Cd_0.5Zn_0.5In₂S₄/S-doped carbon nitride heterojunction: synergistic interfacial charge transfer and local photothermal effect. Acta Physico-Chimica Sinica, 2025, 41(8): 100093-0. doi: 10.1016/j.actphy.2025.100093
13. [13]
  Bing WEI , Jianfan ZHANG , Zhe CHEN . Research progress in fine tuning of bimetallic nanocatalysts for electrocatalytic carbon dioxide reduction. Chinese Journal of Inorganic Chemistry, 2025, 41(3): 425-439. doi: 10.11862/CJIC.20240201
14. [14]
  Jianan Hong , Chenyu Xu , Yan Liu , Changqi Li , Menglin Wang , Yanwei Zhang . Decoding the interfacial competition between hydrogen evolution and CO₂ reduction via edge-active-site modulation in photothermal catalysis. Acta Physico-Chimica Sinica, 2025, 41(9): 100099-0. doi: 10.1016/j.actphy.2025.100099
15. [15]
  Chengqian Mao , Yanghan Chen , Haotong Bai , Junru Huang , Junpeng Zhuang . Photodimerization of Styrylpyridinium Salt and Its Application in Silk Screen Printing. University Chemistry, 2024, 39(5): 354-362. doi: 10.3866/PKU.DXHX202312014
16. [16]
  Siran Wang , Yinuo Wang , Yilong Zhao , Dazhen Xu . Advances in the Application and Preparation of Rhodanine and Its Derivatives. University Chemistry, 2025, 40(5): 318-327. doi: 10.12461/PKU.DXHX202407033
17. [17]
  Qilin YU , Yifei XU , Pengjun ZHANG , Shuwei HAO , Chongqiang ZHU , Chunhui YANG . Effect of regulating K⁺/Na⁺ ratio on the structure and optical properties of double perovskite Cs₂NaBiCl₆: Mn²⁺. Chinese Journal of Inorganic Chemistry, 2025, 41(6): 1058-1067. doi: 10.11862/CJIC.20240418
18. [18]
  Xiting Zhou , Zhipeng Han , Xinlei Zhang , Shixuan Zhu , Cheng Che , Liang Xu , Zhenyu Sun , Leiduan Hao , Zhiyu Yang . Dual Modulation via Ag-Doped CuO Catalyst and Iodide-Containing Electrolyte for Enhanced Electrocatalytic CO₂ Reduction to Multi-Carbon Products: A Comprehensive Chemistry Experiment. University Chemistry, 2025, 40(7): 336-344. doi: 10.12461/PKU.DXHX202412070
19. [19]
  Qiaoqiao BAI , Anqi ZHOU , Xiaowei LI , Tang LIU , Song LIU . Construction of pressure-temperature dual-functional flexible sensors and applications in biomedicine. Chinese Journal of Inorganic Chemistry, 2024, 40(12): 2259-2274. doi: 10.11862/CJIC.20240128
20. [20]
  Jia-He Li , Yu-Ze Liu , Jia-Hui Ma , Qing-Xiao Tong , Jian-Ji Zhong , Jing-Xin Jian . 洛芬碱衍生物的合成、化学发光与重金属离子检测. University Chemistry, 2025, 40(6): 230-237. doi: 10.12461/PKU.DXHX202407080

Get Citation

PDF

XML

Metrics

PDF Downloads(506)
Abstract views(2001)
HTML views(19)

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