Letters in Peptide Science

, Volume 10, Issue 5–6, pp 561–569 | Cite as

Optimisation of peptide-based cytotoxic T-cell determinants using

  • Andrew I. Webb
  • Marie-isabel Aguilar
  • Anthony W. Purcell


In this brief review we describe the methods that our group and others have developed in incorporating non-natural amino acids into peptide antigens, principally to increase protease resistance, for potential use in peptide-based vaccines. Peptide-based vaccination has the potential to generate protective immunity without the need for in situ antigen synthesis or further proteolytic processing of the antigen. The ability to deliver minimal T cell epitopes to the effector cells of the immune system also minimises unwanted side effects and simplifies clinical monitoring. The major hurdle in designing successful peptide-based vaccines resides in issues surrounding the delivery and stability of the peptide immunogen, as it is the form in which the epitope is delivered that will determine how it will be processed by the immune system and ultimately whether it will be capable of inducing an appropriate immune response. Thus, one of the confounding issues with peptide-based vaccines is their poor bioavailability, which is predominantly due to proteolysis and oxidative damage of the `naked' peptide. Strategies that stabilise peptide epitopes promise to overcome the current problems and make peptide-based immunogens more applicable in vaccine design.

cytotoxic T-cells epitope engineering fixed anchor substitution heteroclitic peptides peptidomimetic vaccines 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Doherty, P.C. and Christensen, J.P., Annu. Rev. Immunol., 18 (2000) 561.CrossRefPubMedGoogle Scholar
  2. 2.
    Butz, E.A. and Bevan, M.J., Immunity, 8 (1998) 167.CrossRefPubMedGoogle Scholar
  3. 3.
    Huseby, E.S., Liggitt, D., Brabb, T., Schnabel, B., Ohlen, C. and Goverman, J., J. Exp. Med., 194 (2001) 669.CrossRefPubMedGoogle Scholar
  4. 4.
    Radvanyi, L., Int. Arch. Allergy. Immunol., (2004).Google Scholar
  5. 5.
    Donnelly, J., Berry, K. and Ulmer, J.B., Int. J. Parasitol., 33 (2003) 457. Review.Google Scholar
  6. 6.
    Moss, D.J., Schmidt, C., Elliott, S., Suhrbier, A., Burrows, S. and Khanna, R., Adv. Cancer Res., 69 (1996) 213.PubMedGoogle Scholar
  7. 7.
    Kotb, M., Courtney, H.S., Dale, J.B. and Beachey, E.H., J. Immunol., 142 (1989) 966.PubMedGoogle Scholar
  8. 8.
    Pruksakorn, S., Currie, B., Brandt, E., Phornphutkul, C., Hunsakunachai, S., Manmontri, A., Robinson, J.H., Kehoe, M.A., Galbraith, A. and Good, M.F., Int. Immunol., 6 (1994) 1235.PubMedGoogle Scholar
  9. 9.
    Jackson, D.C., Purcell, A.W., Fitzmaurice, C.J., Zeng, W. and Hart, D.N., Curr. Drug. Targets., 3 (2002) 175.CrossRefPubMedGoogle Scholar
  10. 10.
    Purcell, A.W., Zeng, W., Mifsud, N.A., Ely, L.K., Macdonald, W.A. and Jackson, D.C., J. Pept. Sci., 9 (2003) 255.PubMedGoogle Scholar
  11. 11.
    Oseroff, C., Sette, A., Wentworth, P., Celis, E., Maewal, A., Dahlberg, C., Fikes, J., Kubo, R.T., Chesnut, RW.and Grey, H.M., Alexander J., Vaccine. 16 (1998) 823.CrossRefPubMedGoogle Scholar
  12. 12.
    Tselios, T., Apostolopoulos, V., Daliani, I., Deraos, S., Grdadolnik, S., Mavromoustakos, T., Melachrinou, M., Thymianou, S., Probert, L., Mouzaki, A. and Matsoukas, J.J., Med. Chem., 45 (2002) 275.CrossRefGoogle Scholar
  13. 13.
    Tselios, T., Daliani, I., Deraos, S., Thymianou, S., Matsoukas, E., Troganis, A., Gerothanassis, I., Mouzaki, A., Mavromoustakos, T., Probert L. and Matsoukas, J., Bioorg. Med. Chem. Lett., 10 (2000) 2713.CrossRefPubMedGoogle Scholar
  14. 14.
    Berezhkovskiy, L., Pham, S., Reich, E.P. and Deshpande, S., J. Pept. Res., 54 (1999) 112.CrossRefPubMedGoogle Scholar
  15. 15.
    Leonetti, M., Cotton, J., Leroy, S., Mourier, G. and Menez, A., J. Immunol., 155 (1995) 210.PubMedGoogle Scholar
  16. 16.
    Purcell, A.W., Mol. Immunol., 37 (2000) 483–492.CrossRefPubMedGoogle Scholar
  17. 17.
    Yewdell, J.W. and Bennink, J.R., Annu. Rev. Immunol.,17 (1999) 51CrossRefPubMedGoogle Scholar
  18. 18.
    Rudolf, M.P., Man, S., Melief, C.J., Sette, A. and Kast, W.M., Clin. Cancer Res., 7(sn3 Suppl) (2001) 788s.PubMedGoogle Scholar
  19. 19.
    Wizel, B., Starcher B.C., Samten, B., Chroneos, Z., Barnes, P.F., Dzuris, J., Higashimoto, Y., Appella, E. and Sette, A., J. Immunol., 169(5) (2002) 2524.Google Scholar
  20. 20.
    Kather, A., Ferrara, A., Nonn, M., Schinz, M., Nieland, J., Schneider, A., Durst, M. and Kaufmann, A.M., Int. J. Cancer, 104(3) (2003) 345.CrossRefPubMedGoogle Scholar
  21. 21.
    Caccamo, N., Milano, S., Di Sano, C., Cigna, D., Ivanyi, J., Krensky, A.M., Dieli, F. and Salerno, A.J., Infect Dis., 186(7) (2002) 991.Google Scholar
  22. 22.
    Akiyama, Y., Maruyama, K., Mochizuki, T., Sasaki, K., Takaue, Y. and Yamaguchi, K., Immunol. Lett., 83(1) (2002) 21.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang, Q.J., Huang, X.L., Rappocciolo, G., Jenkins, F.J., Hildebrand, W.H., Fan, Z., Thomas, E.K. and Rinaldo, C.R., Jr., Blood, 99(sn9) (2002) 3360.PubMedGoogle Scholar
  24. 24.
    Frankenberg, N., Pepperl-Klindworth, S., Meyer, R.G. and Plachter, B., Virology, 295(2) (2002) 208.CrossRefPubMedGoogle Scholar
  25. 25.
    Micheletti, F., Monini, P., Fortini, C., Rimessi, P., Bazzaro, M., Andreoni, M., Giuliani, M., Traniello, S., Ensoli, B. and Gavioli, R., Immunology, 106(3) (2002) 395.CrossRefPubMedGoogle Scholar
  26. 26.
    Altfeld, M.A., Livingston, B., Reshamwala, N., Nguyen, P.T., Addo, M.M., Shea, A., Newman, M., Fikes, J., Sidney, J., Wentworth, P., Chesnut, R., Eldridge, R.L., Rosenberg, E.S., Robbins, G.K, Brander, C., Sax, P.E., Boswell, S., Flynn, T., Buchbinder, S., Goulder, P.J., Walker, B.D., Sette, A. and Kalams, S.A., J. Virol., 75(3) (2001) 1301.CrossRefPubMedGoogle Scholar
  27. 27.
    Currier, J.R., deSouza, M., Chanbancherd, P., Bernstein, W., Birx, D.L. and Cox, J.H., J. Virol., 76(10) (2002) 4971.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhao, R. and Collins, E.J., Arch. Immunol, Ther. Exp. (Warsz), 49 (2001) 271. Review.Google Scholar
  29. 29.
    Niedermann, G., Curr. Top. Microbiol. Immunol., 268 (2002) 91–136. Review.PubMedGoogle Scholar
  30. 30.
    Cresswell, P., Bangia, N., Dick, T. and Diedrich, G., Immunol. Rev., 172 (1999) 21.PubMedGoogle Scholar
  31. 31.
    Momburg, F. and Tan, P., Mol. Immunol. 39 (2002) 217.CrossRefPubMedGoogle Scholar
  32. 32.
    Williams, A., Peh, C.A. and Elliott, T., Tissue Antigens, 59 (2002) 3.CrossRefPubMedGoogle Scholar
  33. 33.
    Rammensee, Friede, Stevanovic. Immunogenetics, 41 (1995) 178.CrossRefPubMedGoogle Scholar
  34. 34.
    Brusic, V., Rudy, G., Kyne, A.P. and Harrison, L.C., Nucleic Acids Research, 26(1) (1998) 368.CrossRefPubMedGoogle Scholar
  35. 35.
    Apostolopoulos, V., Karanikas, V., Haurum, J.S. and McKenzie, I.F., J. Immunol., 159 (1997) 5211.PubMedGoogle Scholar
  36. 36.
    Apostolopoulos, V., Haurum, J.S. and McKenzie, I.F., Eur. J. Immunol., 27 (1997) 2579.PubMedGoogle Scholar
  37. 37.
    Apostolopoulos, V., Pietersz, G.A. and McKenzie, I.F., Curr. Opin. Mol. Ther., 1 (1999) 98. Review.PubMedGoogle Scholar
  38. 38.
    Daser, A., Urlaub, H. and Henklein, P., 31 (1994) 331.Google Scholar
  39. 39.
    Mandelboim, O., Bar-Haim, E., Vadai, E., Fridkin, M. and Eisenbach, L., J. Immunol., 159 (1997) 6030.PubMedGoogle Scholar
  40. 40.
    Apostolopoulos, V., Yu, M., Corper, A.L., Teyton, L., Pietersz, G.A., McKenzie I.F., Wilson, I.A. and Plebanski M., J Mol Biol., 318 (2002) 1293.PubMedGoogle Scholar
  41. 41.
    Rubio-Godoy, V., Dutoit, V., Zhao, Y., Simon, R., Guillaume, P., Houghten, R., Romero, P., Cerottini, JC., Pinilla, C. and Valmori, D., Immunol. 169(10) (2002) 5696.Google Scholar
  42. 42.
    Purcell, A.W., Methods. Mol. Biol., 251 (2004) 291.PubMedGoogle Scholar
  43. 43.
    Sahin, U., Tu¨ reci, O¨. and Pfreudschuh, M., Curr. Opin.Immunol., 9 (1997) 709.CrossRefPubMedGoogle Scholar
  44. 44.
    Sette, A., Newman, M., Livingston, B., McKinney, D., Sidney, J., Ishioka, G., Tangri, S., Alexander, J., Fikes, J. and Chesnut, R., Tissue Antigens., 59(6) (2002) 443. Review.CrossRefPubMedGoogle Scholar
  45. 45.
    Mestecky, J. and McGhee, J.R., Adv Immunol 40 (1987) 167.Google Scholar
  46. 46.
    Sette, A. and Fikes, J., Curr. Opin. Immunol., 15 (2003) 461.CrossRefPubMedGoogle Scholar
  47. 47.
    Slansky, J.E., Rattis, F.M., Boyd, L.F., Fahmy, T., Jaffee, E.M., Schneck, J.P., Margulies, D.H. and Pardoll, D.M., Immunity., 13(4) (2000) 529.CrossRefPubMedGoogle Scholar
  48. 48.
    Wang, R., Wang-Zhu, Y., Gabaglia, C.R., Kimachi, K. and Grey, H.M., J. Exp. Med., 190(7) (1999) 983.CrossRefPubMedGoogle Scholar
  49. 49.
    Guichard, G., Zerbib, A., Le Gal, F.A., Hoebeke, J., Connan, F., Choppin, J., Briand, J.P. and Guillet, J.G., J. Med. Chem., 43(20) (2000) 3803.CrossRefPubMedGoogle Scholar
  50. 50.
    Reinelt, S., Marti, M., Dedier, S., Reitinger, T., Folkers, G., de Castro, J.A. and Rognan, D., J. Biol. Chem., 276(27) (2001) 24525.CrossRefPubMedGoogle Scholar
  51. 51.
    Seebach, D. and Matthews, J.L., Chem. Commun., (1997) 2015.Google Scholar
  52. 52.
    Steer, D., Lew, R., Perlmutter, P., Smith, A.I. and Aguilar, M.I., Biochemistry, 41(35) (2002) 10819.CrossRefPubMedGoogle Scholar
  53. 53.
    Steer, D.L., Lew, R.A., Perlmutter, P., Smith, A.I. and Aguilar, M.I., Curr. Med. Chem., 9(8) (2002) 811.Review.CrossRefPubMedGoogle Scholar
  54. 54.
    Aguilar, M., Purcell, A., Webb, A., Perlmutter, P. and Stewart, K., European Peptide Symposium. Sorrento, Italy. S238, P-C53, (2002).Google Scholar
  55. 55.
    Stemmer, C., Quesnel, A., Prevost-Blondel, A., Zimmermann, C., Muller, S., Briand, J.P. and Pircher, H., J. Biol. Chem., 274(9) (1999) 5550.CrossRefPubMedGoogle Scholar
  56. 56.
    Quesnel, A., Zerbib, A., Connan, F., Guillet, J.G., Briand, J.P. and Choppin, J., J. Pept. Sci., 7(3) (2001) 157.Google Scholar
  57. 57.
    Guichard, G., Calbo, S., Muller, S., Kourilsky, P., Briand, J.P. and Abastado, J.P., J. Biol. Chem., 270(44) (1995) 26057.PubMedGoogle Scholar
  58. 58.
    Calbo, S., Guichard, G., Muller, S., Kourilsky, P., Briand, J.P. and Abastado, J.P., J. Immunother., 23(1) (2000) 125.PubMedGoogle Scholar
  59. 59.
    Guichard, G., Connan, F., Graff, R., Ostankovitch, M., Muller, S., Guillet, J.G., Choppin, J. and Briand, J.P., J. Med. Chem., 39(10) (1996) 2030.CrossRefPubMedGoogle Scholar
  60. 60.
    Ostankovitch, M., Guichard, G., Connan, F., Muller, S., Chaboissier, A., Hoebeke, J., Choppin, J., Briand, J.P.and Guillet, J.G., J. Immunol., 161(1) (1998) 200.PubMedGoogle Scholar
  61. 61.
    Webby, R.J., Andreansky, S., Stambas, J., Rehg, J.E., Webster, R.G., Doherty, P.C. and Turner, S.J., Proc. Natl. Acad. Sci. U.S.A., 100(12) (2003) 7235.CrossRefPubMedGoogle Scholar
  62. 62.
    Beck, A., Bussat, M.C., Klinguer-Hamour, C., Goetsch, L., Aubry, J.P., Champion, T., Julien, E., Haeuw, J.F., Bonnefoy, J.Y. and Corvaia, N., J. Pept. Res., 57(6) (2001) 528.CrossRefPubMedGoogle Scholar
  63. 63.
    Marschutz, M.K., Zauner, W., Mattner, F., Otava, A., Buschle, M. and Bernkop-Schnurch, A., Peptides, 23(10) (2002) 1727.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2003

Authors and Affiliations

  • Andrew I. Webb
    • 1
  • Marie-isabel Aguilar
    • 1
  • Anthony W. Purcell
    • 1
  1. 1.Department of Biochemistry and Molecular BiologyMonash UniversityAustralia

Personalised recommendations