Design of amyloidogenic peptide traps

Abstract

Segments of proteins with {beta}-strand propensity can self associate to form amyloid fibrils associated with many diseases. These regions often adopt alternative structures in their folded states, or are intrinsically disordered in solution, making it difficult to generate binders or inhibitors with existing strategies. Here we describe a general approach to bind such segments in {beta}-strand and {beta}-hairpin conformations using de novo designed scaffolds that contain deep peptide binding clefts flanked by {beta}-strands that form hydrogen bonds to the peptide upon binding. The designs bind their cognate peptides in vitro with nanomolar affinities and in mammalian cells. The crystal structure of a designed protein-peptide complex is close to the design model, and NMR characterization reveals how the peptide binding cleft is protected in the apo state. We use the approach to design binders to segments of the amyloid forming proteins Transthyretin, Tau, Serum amyloid A1 and A{beta}42. The A{beta} binders block assembly of A{beta} fibrils as effectively as the most potent of the clinically tested antibodies to date.