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
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