Max Bergmann lecture protein epitope mimetics in the age of structural vaccinology.
This review highlights the growing importance of protein epitope mimetics in the discovery of new biologically active molecules and their potential applications in drug and vaccine research. The focus is on folded β-hairpin mimetics, which are designed to mimic β-hairpin motifs in biologically important peptides and proteins. An ever-growing number of protein crystal structures reveal how β-hairpin motifs often play key roles in protein-protein and protein-nucleic acid interactions. This review illustrates how using protein structures as a starting point for small-molecule mimetic design can provide novel ligands as protein-protein interaction inhibitors, as protease inhibitors, and as ligands for chemokine receptors and folded RNA targets, as well as novel antibiotics to combat the growing health threat posed by the emergence of antibiotic-resistant bacteria. The β-hairpin antibiotics are shown to target a β-barrel outer membrane protein (LptD) in Pseudomonas sp., which is essential for the biogenesis of the outer cell membrane. Another exciting prospect is that protein epitope mimetics will be of increasing importance in synthetic vaccine design, in the emerging field of structural vaccinology. Crystal structures of protective antibodies bound to their pathogen-derived epitopes provide an ideal starting point for the design of synthetic epitope mimetics. The mimetics can be delivered to the immune system in a highly immunogenic format on the surface of synthetic virus-like particles. The scientific challenges in molecular design remain great, but the potential significance of success in this area is even greater.
Chemistry Department, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland. robinson@oci.uzh.ch
John A
JA
Robinson
D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology; D017433:Protein Structure, Secondary; D014614:Vaccines, Synthetic / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D000939:Epitopes; D010446:Peptide Fragments; D014614:Vaccines, Synthetic