title: Synthetic virus-like particles and conformationally constrained peptidomimetics in vaccine design.
abstract: Conformationally constrained peptidomimetics could be of great value in the design of vaccines targeting protective epitopes on viral and bacterial pathogens. But the poor immunogenicity of small synthetic molecules represents a serious obstacle for their use in vaccine development. Here, we show how a constrained epitope mimetic can be rendered highly immunogenic through multivalent display on the surface of synthetic virus-like nanoparticles. The target epitope is the V3 loop from the gp120 glycoprotein of HIV-1 bound to the neutralizing antibody F425-B4e8. The antibody-bound V3 loop adopts a β-hairpin conformation, which is effectively stabilized by transplantation onto a D-Pro-L-Pro template. The resulting mimetic after coupling to synthetic virus-like particles elicited antibodies in rabbits that recognized recombinant gp120. The elicited antibodies also blocked infection by the neutralization sensitive tier-1 strain MN of HIV-1, as well as engineered viruses with the V1V2 loop deleted; this result is consistent with screening of V3 by the V1V2 loop in intact trimeric viral gp120 spikes. The results provide new insights into HIV-1 vaccine design based on the V3 loop, and illustrate how knowledge from structural biology can be exploited for the design of constrained epitope mimetics, which can be delivered to the immune system by using a highly immunogenic synthetic nanoparticle delivery system.
authors.affiliation: Chemistry Department, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Tina
authors.initials: T
authors.lastname: Riedel
authors.forename: Arin
authors.initials: A
authors.lastname: Ghasparian
authors.forename: Kerstin
authors.initials: K
authors.lastname: Moehle
authors.forename: Peter
authors.initials: P
authors.lastname: Rusert
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
authors.forename: John A
authors.initials: JA
authors.lastname: Robinson
mesh_terms: D016915:AIDS Vaccines; D000595:Amino Acid Sequence; D004797:Enzyme-Linked Immunosorbent Assay; D015699:HIV Envelope Protein gp120 / Q000737:chemistry; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014614:Vaccines, Synthetic; D014771:Virion
chemical_list: D016915:AIDS Vaccines; D015699:HIV Envelope Protein gp120; D010455:Peptides; D014614:Vaccines, Synthetic