Immunosuppressory activity of the cyclodimeric peptide with RGD-sequences.

• Authors: Zbigniew Szewczuk , Paweł Buczek , Piotr Stefanowicz , Krzysztof Krajewski , Zbigniew Wieczore , Ignacy Z Siemion
• Languages of publication: EN

Abstracts

EN

Our previous studies showed that the nonapeptide fragment of HLA-DQ of the sequence H-Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr-OH, located in the β164-172 loop, strongly suppresses the humoral and cellular immune responses, while its shorter analogs, H-Arg-Gly-Asp-Val-OH, H-Arg-Gly-Asp-Val-Tyr-OH and H-Gln-Arg-Gly-Asp-Val-Tyr-OH show only a weak stimulatory activity in respect to the humoral immunological response. These fragments contain the Arg-Gly-Asp (RGD) sequence, known for its importance for cellular association phenomena. Based on the crystal structure of HLA-DR1, we also designed and synthesized a cyclic analog H-Cys-Arg-Gly-Asp-Val-Tyr-Cys-OH with restricted conformation, which strongly suppresses the immune response and selectively inhibits the αvβ3 integrin, suggesting that the mechanism of the immunosuppressory action of the peptide is associated with inhibition of the integrin. In this paper we present the design and synthesis of the cyclodimeric peptide, Arg-Gly-Asp-Arg-Gly-Asp, which is also known as a selective αvβ3 inhibitor. The synthesized peptide strongly suppresses both the humoral and cellular immune response. The results support our hypothesis that the immunomodulatory activity of HLA-DQ fragments may be connected with their interactions with some particular integrins on the cell surface.

Keywords

EN

dimeric analog; chemical synthesis; homodetic cyclization; histocompatibility antigen; HLA-DQ; RGD-sequence; MHC class-II

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2001
• Volume: 48
• Issue: 1
• Pages: 121-130

Dates

published

2001

received

2000-11-2

revised

2001-02-1

accepted

2001-02-15

Contributors

author

Zbigniew Szewczuk

• Faculty of Chemistry, University of Wrocław, Wrocław, Poland

author

Paweł Buczek

• Faculty of Chemistry, University of Wrocław, Wrocław, Poland

author

Piotr Stefanowicz

• Faculty of Chemistry, University of Wrocław, Wrocław, Poland

author

Krzysztof Krajewski

• Faculty of Chemistry, University of Wrocław, Wrocław, Poland

author

Zbigniew Wieczore

• Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland

author

Ignacy Z Siemion

• Faculty of Chemistry, University of Wrocław, Wrocław, Poland

References

• Bisang, C., Weber, C., Inglis, J., Schiffer, C.A., van Gunsteren, H.F., Jelesarov, I., Bosshard, H.R. & Robinson, J.A. (1995) Stabilization of type 1 β-turn conformations in peptides containing the NPNA- repeat motif of the Plasmodium falciparum circumsporozoite protein by substituting proline for (S)-α-methylproline. J. Am. Chem. Soc. 117, 7904-7915.
• Bodanszky, M. & Bodanszky, A. (1985) The Practice of Peptide Synthesis. Springer-Verlag, Berlin.
• Brown, J.H., Jardetzky, T.S., Gorga, J.C., Stern, L.J., Urban, R.G., Strominger, J.L. & Wiley, D.C. (1993) 3-Dimensional structure of the human class-II histocompatibility antigen HLA- DR1. Nature 364, 33-39.
• Burgess, K., Lim, D. & Mousa, S.A. (1996) Synthesis and solution conformation of cyclo[RGDRGD]: A cyclic peptide with selectivity for the alpha V beta 3 receptor. J. Med. Chem 39, 4520-4526.
• Cebrat, M., Wieczorek, Z. & Siemion, I.Z. (1996) Immunosuppressive activity of hymenistatin I. Peptides 17, 191-196.
• Dianzani, U. & Malavasi, F. (1995) Lymphocyte adhesion to endothelium. Crit. Rev. Immunol. 15, 167-200.
• Gorga, J.C. (1992) Structural analysis of class II major histocompatibility complex proteins. Crit. Rev. Immunol. 11, 305-335.
• Lagrange, P.H., Macksaness, G.B., Miller, T.E. & Pardon, P. (1974) Influence of dose and route of antigen injection on the immunological induction of T cells. J. Exp. Med. 139, 528-542.
• Mishell, R.I. & Dutton, R.W. (1967) Immunization of dissociated spleen cell cultures from normal mice. J. Exp. Med. 126, 423-428.
• Perczel, A. & Fasman, G.D. (1992) Quantitive analysis of cyclic β-turn models. Protein Sci. 1, 378-395.
• Pfaff, M., Tangemann, K., Muller, B., Gurrath, M., Muller, G., Kessler, H., Timpl, R. & Engel, J. (1994) Selective recognition of cyclic RGD peptides of NMR defined conformation by alpha IIb beta 3, alpha V beta 3, and alpha 5 beta 1 integrins. J. Biol. Chem. 269, 20233-20238.
• Ruoslahti, E. (1996) RGD and other recognition sequences for integrins. Annu. Rev. Cell. Dev. Biol. 12, 697-715.
• Schlagel, L.J., Bors, L., Mitchell, G.W., King, J.L., Cao, L., Kirk, M. & Whitaker, J.N. (1997) Immunological effects of an arginine side chain contaminating synthetically prepared peptides. Molec. Immunol. 34, 185-194.
• Schwyzer, R. & Sieber, P. (1958) Homodetic cyclo-polypeptides VI. A synthetic analog of gramicidin S: cyclobis (L-valyl-L-lysyl-L-leucyl-D-phenylalanyl- L-prolyl). Helv. Chim. Acta 41, 1582-1587.
• Stewart, M., Thiel, K. & Hogg, N. (1995) Leukocyte integrins. Curr. Opin Cell Biol. 7, 690-696.
• Szewczuk, Z., Siemion, I.Z. & Wieczorek, Z. (1996a) Immunological properties of the thymopentin-like fragments of HLA-DQ. Mol. Immunol. 33, 903-908.
• Szewczuk, Z., Stefanowicz, P., Wilczyński, A., Siemion, I.Z., Cierniewski, C.S., Kralisz, U. & Wieczorek, Z. (1996b) The immunosuppressory and adhesive mini-region of the human major histocompatibility protein, HLA-DQ. Biopolymers 40, 571-583.
• Szewczuk, Z., Wieczorek, Z., Stefanowicz, P., Wilczyński, A. & Siemion, I.Z. (1997) Further investigations on thymopentin-like fragments of HLA-DQ and their analogues. Arch. Immunol. Ther. Exp. (Warsz) 45, 335-341.
• Szewczuk, Z., Wilczyński, A., Stefanowicz, P., Fedorowicz, W., Siemion, I.Z. & Wieczorek, Z. (1999) Immunosuppressory mini-regions of HLA-DP and HLA-DR. Mol. Immunol. 36, 525-533.
• Wieczorek, Z., Voelter, W., Nawrocka-Bolewska, E., Zimecki, M. & Siemion, I.Z. (1991) The unusually high immunomodulatory activity of thymopentin analogue Pro5-TP-5. Mol. Immunol. 28, 95-98.