X-ray studies as well as structure-activity relationships indicate that the
central part of class I MHC-binding nonapeptides represents the main inter
action site for a T cell receptor. In order to rationally manipulate T cell
epitopes, several nonpeptidic spacer have been designed from the X-ray str
ucture of a MHC-peptide complex and substituted for the T cell receptor-bin
ding part of several antigenic peptides. The binding of the modified epitop
es to the HLA-B*2705 protein was studied by an in vitro stabilisation assay
and the thermal stability of all complexes examined by circular dichroism
spectroscopy. Depending on their chemical nature and length, the introduced
spacers may be classified into two categories. Monofunctional spacers (11-
amino undecanoate, (R)-3-hydroxybutyrate trimer) simply link two anchoring
peptide positions (P3 and P9) but loosely contact the MHC binding groove, a
cid thus decrease more or less the affinity of the altered epitopes to HLA-
B*2705. Bifunctional spacers ((R)-3-hydroxybutyrate and beta-homoalanine co
mbinations) not only bridges the two distant anchoring amino acids but also
strongly interact with the binding cleft and lead to an increase in bindin
g to the MHC protein. The presented modified ligands constitute interesting
tools for perturbing the T cell response to the parent antigenic peptide.