ABSTRACT Fatty acylation of peptides can dramatically enhance immune responses to those peptides. In most studies looking at enhancing immune responses by fatty acylation of peptides, between one to three palmitic acid moieties have been attached to the N-terminus of the peptides either directly via an amide bond (N-palmitoylated) or via S-glyceryl cysteine. Lipopeptides synthesized with these types of linkages appear to preferentially induce CD8+ cytotoxic T cells when injected into animals. Recently, it has been reported that peptides palmitoylated via the much more labile thioester bond (thiopalmitoylated), can enhance antibody production and CD4+ helper T cell responses significantly more than N-palmitoylated peptides. Thiopalmitoylation is a common post-translational modification of numerous proteins within the body. Interestingly, many of the proteins that have been identified as putative autoantigens in a variety of T cell-mediated autoimmune diseases are thiopalmitoylated, and we have proposed that thiopalmitoylated peptides might be more likely than other peptides released during autoimmune-mediated tissue damage to break down self-tolerance and induce autoimmune disease due to the adjuvant-like effects of the attached fatty acids. Because of these adjuvant-like effects, thiopalmitoylated lipopeptides have a potential application in vaccine development, and could thus provide a novel approach to development of human peptide vaccines.
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