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]
  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
2. [2]
  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
3. [3]
  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
4. [4]
  Jiaxin Su , Jiaqi Zhang , Shuming Chai , Yankun Wang , Sibo Wang , Yuanxing Fang . Optimizing Poly(heptazine imide) Photoanodes Using Binary Molten Salt Synthesis for Water Oxidation Reaction. Acta Physico-Chimica Sinica, 2024, 40(12): 2408012-. doi: 10.3866/PKU.WHXB202408012
5. [5]
  Kexin Dong , Chuqi Shen , Ruyu Yan , Yanping Liu , Chunqiang Zhuang , Shijie Li . Integration of Plasmonic Effect and S-Scheme Heterojunction into Ag/Ag₃PO₄/C₃N₅ Photocatalyst for Boosted Photocatalytic Levofloxacin Degradation. Acta Physico-Chimica Sinica, 2024, 40(10): 2310013-. doi: 10.3866/PKU.WHXB202310013
6. [6]
  Haiyu Nie , Chenhui Zhang , Fengpei Du . Ideological and Political Design for the Preparation, Characterization and Particle Size Control Experiment of Nanoemulsion. University Chemistry, 2024, 39(2): 41-46. doi: 10.3866/PKU.DXHX202306055
7. [7]
  Xingyang LI , Tianju LIU , Yang GAO , Dandan ZHANG , Yong ZHOU , Meng PAN . A superior methanol-to-propylene catalyst: Construction via synergistic regulation of pore structure and acidic property of high-silica ZSM-5 zeolite. Chinese Journal of Inorganic Chemistry, 2024, 40(7): 1279-1289. doi: 10.11862/CJIC.20240026
8. [8]
  Yanhui XUE , Shaofei CHAO , Man XU , Qiong WU , Fufa WU , Sufyan Javed Muhammad . Construction of high energy density hexagonal hole MXene aqueous supercapacitor by vacancy defect control strategy. Chinese Journal of Inorganic Chemistry, 2024, 40(9): 1640-1652. doi: 10.11862/CJIC.20240183
9. [9]
  Fei Xie , Chengcheng Yuan , Haiyan Tan , Alireza Z. Moshfegh , Bicheng Zhu , Jiaguo Yu . d带中心调控过渡金属单原子负载COF吸附O₂的理论计算研究. Acta Physico-Chimica Sinica, 2024, 40(11): 2407013-. doi: 10.3866/PKU.WHXB202407013
10. [10]
  Zongfei YANG , Xiaosen ZHAO , Jing LI , Wenchang ZHUANG . Research advances in heteropolyoxoniobates. Chinese Journal of Inorganic Chemistry, 2024, 40(3): 465-480. doi: 10.11862/CJIC.20230306
11. [11]
  Baohua LÜ , Yuzhen LI . Anisotropic photoresponse of two-dimensional layered α-In₂Se₃(2H) ferroelectric materials. Chinese Journal of Inorganic Chemistry, 2024, 40(10): 1911-1918. doi: 10.11862/CJIC.20240105
12. [12]
  Shengbiao Zheng , Liang Li , Nini Zhang , Ruimin Bao , Ruizhang Hu , Jing Tang . Metal-Organic Framework-Derived Materials Modified Electrode for Electrochemical Sensing of Tert-Butylhydroquinone: A Recommended Comprehensive Chemistry Experiment for Translating Research Results. University Chemistry, 2024, 39(7): 345-353. doi: 10.3866/PKU.DXHX202310096
13. [13]
  Zhibei Qu , Changxin Wang , Lei Li , Jiaze Li , Jun Zhang . Organoid-on-a-Chip for Drug Screening and the Inherent Biochemistry Principles. University Chemistry, 2024, 39(7): 278-286. doi: 10.3866/PKU.DXHX202311039
14. [14]
  Hong Zheng , Xin Peng , Chunwang Yi . The Tale of Caprolactam Cyclic Oligomers: The Ever-changing Life of “Princess Cyclo”. University Chemistry, 2024, 39(9): 40-47. doi: 10.12461/PKU.DXHX202403058
15. [15]
  Xinyi Hong , Tailing Xue , Zhou Xu , Enrong Xie , Mingkai Wu , Qingqing Wang , Lina Wu . Non-Site-Specific Fluorescent Labeling of Proteins as a Chemical Biology Experiment. University Chemistry, 2024, 39(4): 351-360. doi: 10.3866/PKU.DXHX202310010
16. [16]
  Nana Wang , Gaosheng Zhang , Huosheng Li , Tangfu Xiao . Discussion on the Teaching Reform of Environmental Functional Materials within the Context of “Double First-Class” Initiative: Emphasizing the Integration of Industry, Academia, Research, and Application. University Chemistry, 2024, 39(6): 137-144. doi: 10.3866/PKU.DXHX202312010
17. [17]
  Chunmei GUO , Weihan YIN , Jingyi SHI , Jianhang ZHAO , Ying CHEN , Quli FAN . Facile construction and peroxidase-like activity of single-atom platinum nanozyme. Chinese Journal of Inorganic Chemistry, 2024, 40(9): 1633-1639. doi: 10.11862/CJIC.20240162
18. [18]
  Qiangqiang SUN , Pengcheng ZHAO , Ruoyu WU , Baoyue CAO . Multistage microporous bifunctional catalyst constructed by P-doped nickel-based sulfide ultra-thin nanosheets for energy-efficient hydrogen production from water electrolysis. Chinese Journal of Inorganic Chemistry, 2024, 40(6): 1151-1161. doi: 10.11862/CJIC.20230454
19. [19]
  Yihao Zhao , Jitian Rao , Jie Han . Synthesis and Photochromic Properties of 3,3-Diphenyl-3H-Naphthopyran: Design and Teaching Practice of a Comprehensive Organic Experiment. University Chemistry, 2024, 39(10): 149-155. doi: 10.3866/PKU.DXHX202402050
20. [20]
  Tianlong Zhang , Rongling Zhang , Hongsheng Tang , Yan Li , Hua Li . Online Monitoring and Mechanistic Analysis of 3,5-diamino-1,2,4-triazole (DAT) Synthesis via Raman Spectroscopy: A Recommendation for a Comprehensive Instrumental Analysis Experiment. University Chemistry, 2024, 39(6): 303-311. doi: 10.3866/PKU.DXHX202312006

Get Citation

PDF

XML

Metrics

PDF Downloads(506)
Abstract views(1889)
HTML views(10)

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