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J Biol Chem, Vol. 274, Issue 15, 10227-10234, April 9, 1999

A Structure-based Approach to Designing Non-natural Peptides That Can Activate Anti-melanoma Cytotoxic T Cells

Maha Ayyoub, Honoré Mazarguil, Bernard Monsarrat, Benoît Van den Eynde^§, and Jean Edouard Gairin

From the  Institut de Pharmacologie et Biologie Structurale, UPR 9062 CNRS, 205 route de Narbonne, 31400 Toulouse, France and the ^§ Ludwig Institute for Cancer Research, Brussels Branch, B-1200 Brussels, Belgium

Tumor antigens presented by major histocompatibility complex (MHC) class I molecules and recognized by CD8⁺ cytotoxic T lymphocytes (CTLs) may generate an efficient antitumor immune response after appropriate immunization. Antigenic peptides can be used in vivo to induce antitumor or antiviral immunity. The efficiency of naked peptides may be greatly limited by their degradation in the biological fluids. We present a rational, structure-based approach to design structurally modified, peptidase-resistant and biologically active analogues of human tumor antigen MAGE-1.A1. This approach is based on our understanding of the peptide interaction with the MHC and the T cell receptor and its precise degradation pathway. Knowledge of these mechanisms led to the design of a non-natural, minimally modified analogue of MAGE-1.A1, [Aib²,NMe-Ser⁸]MAGE-1.A1, which was highly peptidase-resistant and bound to MHC and activated MAGE-1.A1-specific anti-melanoma CTLs. Thus, we showed that it is possible to structurally modify peptide epitopes to obtain analogues that are still specifically recognized by CTLs. Such analogues may represent interesting leads for antitumor synthetic vaccines.

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