title: Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases.
abstract: Synthetic peptide immunogens that 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 the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter 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 that 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 disease.
authors.affiliation: AC Immune SA, PSE-B, EPFL, CH-1015 Lausanne, Switzerland.
authors.forename: David T
authors.initials: DT
authors.lastname: Hickman
authors.forename: María Pilar
authors.initials: MP
authors.lastname: López-Deber
authors.forename: Dorin Mlaki
authors.initials: DM
authors.lastname: Ndao
authors.forename: Alberto B
authors.initials: AB
authors.lastname: Silva
authors.forename: Deepak
authors.initials: D
authors.lastname: Nand
authors.forename: Maria
authors.initials: M
authors.lastname: Pihlgren
authors.forename: Valérie
authors.initials: V
authors.lastname: Giriens
authors.forename: Rime
authors.initials: R
authors.lastname: Madani
authors.forename: Annie
authors.initials: A
authors.lastname: St-Pierre
authors.forename: Hristina
authors.initials: H
authors.lastname: Karastaneva
authors.forename: Luitgard
authors.initials: L
authors.lastname: Nagel-Steger
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
authors.forename: Detlev
authors.initials: D
authors.lastname: Riesner
authors.forename: Claude
authors.initials: C
authors.lastname: Nicolau
authors.forename: Marc
authors.initials: M
authors.lastname: Baldus
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeifer
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D002942:Circular Dichroism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D057165:Proteostasis Deficiencies / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry; D014612:Vaccines / Q000737:chemistry*
chemical_list: D052160:Benzothiazoles; D007074:Immunoglobulin G; D008081:Liposomes; D010455:Peptides; D013844:Thiazoles; D014612:Vaccines; C009462:thioflavin T