IFN-gamma-derived lipopeptides: influence of lipid modification on the conformation and the ability to induce MHC class II expression on murine and human cells.

Two truncated analogues of a previously identified lipopeptide agonist toward the IFN-gamma receptor were synthesized in an attempt to determine the minimal compound able to induce expression of MHC class II molecules on murine and human cells and to study the role of the lipid tail. Circular dichroism studies were used to probe the induced conformationnal changes. Our results indicate at least a double role for the lipid modification that contributes to the stabilization of helical organization of the associated peptide and to its passive delivery into the cytoplasm. The persistence of biological activity in a truncated peptide of half of the residues present in the lead compound suggests that the lipid tail could also contribute to the stabilization of the peptide-receptor binding through additional hydrophobic interactions. This study allowed to readjust the minimal requirements for intracellular IFN-gamma receptor stimulation. More generally, we suggest that lipidated analogues of functional peptides could be utilized for intracellular target validation in the drug discovery process.