Conformation-specific antibodies that recognize toxic aggregated proteins associated with neurodegenerative disorders (e.g., Parkinson's disease) are invaluable for therapeutic and diagnostic applications. We have developed a novel approach for designing domain antibodies specific for misfolded proteins that is inspired by the molecular interactions mediating protein aggregation. We find that grafting small hydrophobic peptides from several amyloidogenic polypeptides (e.g., Alzheimer's A� and Parkinson's aSynuclein) into the complementarity-determining regions of domain antibodies generates Grafted AMyloid-Motif AntiBODIES (gammabodies) that recognize aggregated proteins with nanomolar binding affinity (Perchiacca et al., PNAS, 2012). Gammabodies bind selectively to aggregates containing the cognate peptide motifs via homotypic interactions. We will discuss our current efforts to optimize the identity, length, location and number of grafted amyloid peptides within single- and multidomain gammabodies to further enhance binding affinity and specificity.

Structure-based design of domain antibodies specific for misfolded proteins

245th National Meeting (2013)

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