Molecular mimetics of Neisseria meningitidis serogroup B polysaccharide.
Strains of Neisseria meningitidis serogroup B (NmB) are an important cause of meningitis and sepsis. Efforts to develop a NmB vaccine have been hampered by poor immunogenicity of the polysaccharide capsule, which cross-reacts with host polysialic acid, and the danger of eliciting autoantibodies. To investigate the potential of molecular mimetics to circumvent these problems, we prepared murine monoclonal antibodies (mAbs) against the N-propionyl derivative (N-Pr) of NmB polysaccharide. Several mAbs were found that reacted with capsular polysaccharide epitopes, which were distinct from host polysialic acid. These mAbs also passively conferred protection against experimental bacteremia. We used these mAbs to screen novel independently folding peptide phage display libraries, and pools of combinatorial small molecules, each consisting of approximately 30 to approximately 700 small molecules of diverse composition. To date, several mimetic candidates have been identified. One is a peptide selected from a library of independently folding alphabeta peptides, and others are peptoid dimers or trimers selected from the small molecule pools. The peptoids contain an indan-type of ring system, and some of them also contain a large hydrophobic group such as oleyl amine or dehydroabietyl amine, and a positively charged group at the amino-terminus. Both the alphabeta peptide from the phage library, and the peptoids from the small molecule pools, inhibit binding of the mAbs to N-Pr NmB polysaccharide. Future studies will focus on the structure/activity relationship of these mimetics, and the development of immunogens that may be capable of eliciting anticapsular antibody without autoantibody activity.
Moe
G R
GR
Children's Hospital Oakland Research Institute, CA 94609, USA. gmoe@chori.org
Granoff
D M
DM
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D022401:Meningococcal Vaccines / Q000276:immunology / Q000302:isolation & purification; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009345:Neisseria meningitidis / Q000145:classification / Q000276:immunology*; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D034444:Peptoids; D011135:Polysaccharides, Bacterial / Q000276:immunology*; D017510:Protein Folding; D017433:Protein Structure, Secondary
D000911:Antibodies, Monoclonal; D000939:Epitopes; D022401:Meningococcal Vaccines; D019151:Peptide Library; D010455:Peptides; D034444:Peptoids; D011135:Polysaccharides, Bacterial