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 towa rd the IFN-gamma receptor were synthesized in an attempt to determine the m inimal compound able to induce expression of MHC class II molecules on muri ne and human cells and to study the role of the lipid tail. Circular dichro ism studies were used to probe the induced conformationnal changes. Our res ults indicate at least a double role for the lipid modification that contri butes to the stabilization of helical organization of the associated peptid e and to its passive delivery into the cytoplasm. The persistence of biolog ical 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 st abilization of the peptide-receptor binding through additional hydrophobic interactions. This study allowed to readjust the minimal requirements for i ntracellular IFN-gamma receptor stimulation. More generally, we suggest tha t lipidated analogues of functional peptides could be utilized for intracel lular target validation in the drug discovery process.