DOI QR코드

DOI QR Code

Design, Syntheses, and Conformational Study of Angiogenesis Inhibitors


초록

Since anti-angiogenesis could lead to the suppression of tumor growth, angiogenesis inhibitors have received particular attention for their therapeutic potential. In this study, two angiogenic inhibitors using the bioactive sequence from the kring le 5, AK1(KLYDY), AK2(KLWDF) were designed and synthesized. We have investigated their solution structures using NMR spectroscopy and their activities as angiogenesis inhibitors. AK2 has an intramolecular hydrogen bon d between the side chain amino proton of Lys1 and the carboxyl oxygen of Asp4 with a N ${\cdot}{\cdot}{\cdot}$O distance of $3.27\AA$, while AK1 shows more flexible structures than AK2. Indole ring in Trp is much bigger than the phenyl ring in Tyr and may have good face-to-edge interaction enforcing more rigid and constrained conformational features of AK2. Because of this relatively stable structure, Trp3 in AK2 may have better hydrophobic interaction with Phe5 than Tyr3 in AK1 if two adjacent aromatic groups are located in hydrophobic pocket of receptor. Since AK2 shows the similar anti-angiogenic activities to AK1, we are also able to confirm that the activity of AK1 is irrelevant to the Tyr phosphorylation. More rigid drug with higher activities can be provided by the mimetic approaches. For the further development of the angiogenesis inhibitors, these conformational studies on our lead peptides will be helpful in design of peptidomimetics.

키워드

참고문헌

  1. Nat. Med. v.1 Folkman, J.
  2. Harvey Lect. Ser. v.92 Folkman, J.
  3. Drugs v.58 no.1 Gasparini, G.
  4. J. Clin. Pharmacol. v.38 no.10 Gibaldi, M.
  5. Cancer Res. v.57 no.7 Sim, B. K.; O'Reilly, M. S.; Liang, H.; Fortier, A. H.; He,W.; Madsen, J. W.; Lapcevich, R.; Nacy, C. A.
  6. Science v.284 Bergers, G.; Javaherian, K.; Lo, K.; Folkman, J.; Hanahan,D.
  7. Cold Spring Harb. Symp. Quant. Biol. v.59 O'Reilly, M. S.; Holmgren, L.; Shing, Y.; Chen, C.;Rosenthal, R. A.; Cao, Y.; Moses, M.; Lane, W. S.; Sage,E. H.; Folkman, J.
  8. J. Biol. Chem. v.272 Cao, Y.; Chen, A.; An, S. S.; Ji, R. W.; Davidson, D.;Llinas, M.
  9. Biochem. Biophys. Res. Commun. v.258 Lu, H.; Dhanabal, M.; Volk, R.; Waterman, M. J.;Ramchandran, R.; Knebelmann, B.; Segal, M.; Sukhatme,V. P.
  10. Biochem. Biophys. Res. Commun. v.247 no.2 Ji, W. R.; Barrientos, L. G.; Llinas, M.; Gray, H.; Villarreal,X.; DeFord, M. E.; Castellino, F. J.; Kramer, R. A.; Trail,P. A. Biochem.
  11. Biochemistry v.37 no.10 Chang, Y.; Mochalkin, I.; McCance, S. G.; Cheng, B.;Tulinsky, A.; Castellim, F. J.
  12. Arch.Biochem. Biophys. v.375 no.2 Lee, H.; Kim, H. K.; Lee, J. H.; You, W. K.; Chung, S. I.;Chang, S. I.; Park, M. H.; Hong, Y. K.; Joe, Y. A.
  13. et al. International Patent WO v.97. Davidson, D. J.
  14. Cancer Letters v.113 Suh, H. S.; Jung, E.-J.; Kim, T.-H.; Lee, H.-Y.; Park, Y.-H.; Kim, K.-W.
  15. Cancer Res. v.56 Strawn, L. M.; McMahon, G.; App, H.; Schreck, R.;Kuchler, W. R.; Longhi, M. P.; Hui, T. H.; Tang, C.;Levitzki, A.; Gazit, A.; Chen, I.; Keri, G.; Orfi, L.; Risau,W.; Flamme, I.; Ullrich, A.; Hirth, K. P.; Shawver, L. K.
  16. J. Magn. Reson. v.88 Derome, A.; Willamson, M.
  17. J. Magn. Reson. v.65 Bax, A.; Davis, D. G.
  18. Mol. Phys. v.41 Macura, S.; Ernst, R. R.
  19. J. Magn. Reson. v.63 Bax, A.; Davis, D. G.
  20. J. Chem. Phys. Lett. v.69 Bodenhausen, G.; Ruben, D. J.
  21. Crit. Rev.Biochem. Mol. Biol. v.24 Clore, G. M.; Gronenborn, A. M. CRC
  22. Protein Sci. v.3 Clore, G. M.; Gronenborn, A. M.
  23. X-PLOR Manual, Version 3.1 Brunger, A. T.
  24. J. Mol. Biol. v.169 Wuthrich, K.; Billeter, M.; Braun, W. J.
  25. Biochemistry v.26 Clore, G. M.; Gronenborn, A. M.; Nilges, M.; Ryan, C. A.
  26. FEBS Lett. v.229 Nilges, M.; Clore, G. M.; Gronenborn, A. M.
  27. J. Biomol. NMR v.2 Kuszewski, J.; Nilges, M.; Brunger, A. T.
  28. NMR of Protein and Nucleic Acid Wuthrich, K.
  29. J. Am. Chem. Soc. v.106 Knoche, L. M.
  30. J. Am. Chem.Soc. v.1112 Gellman, S. H.; Adams, B. R.; Dado, G. P.

피인용 문헌

  1. Structural and Functional Characterization of CRAMP-18 Derived from a Cathelicidin-Related Antimicrobial Peptide CRAMP vol.24, pp.10, 2001, https://doi.org/10.5012/bkcs.2003.24.10.1478
  2. In vitro Interaction of Recombinantly Expressed Kringle 5 (rK5) with Ras Guanine Nucleotide Dissociation Stimulator-like Factor (Rgl2) vol.25, pp.12, 2001, https://doi.org/10.5012/bkcs.2004.25.12.1863
  3. Angiogenesis Inhibitor Derived from Angiostatin Active Sites vol.25, pp.9, 2001, https://doi.org/10.5012/bkcs.2004.25.9.1331
  4. Kringle 5 peptide-albumin conjugates with anti-migratory activity vol.14, pp.4, 2001, https://doi.org/10.1016/j.bmcl.2003.12.025