Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases

Abstract

Synthetic peptide immunogens which mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that both the peptide lipidation pattern, lipid anchor chain length as well as the liposome surface charge, significantly alters peptide conformation. Peptide aggregation could also be modulated post- liposome assembly by the addition of distinct small-molecule β-sheet breakers. Immunization of both mice and monkeys with a model liposomal vaccine containing β-sheet aggregated lipopeptide (Palm1-15) induced polyclonal IgG antibodies which specifically recognized β-sheet multimers over monomer or non-pathological native protein. The rational design of liposome-bound peptide immunogens with defined conformation opens up the possibility to generate vaccines against a range of protein misfolding diseases such as Alzheimer’s disease.