Specific keratinase derived designer peptides potently inhibit A β aggregation resulting in reduced neuronal toxicity and apoptosis

Compelling evidence implicates self-assembly of amyloid- (A ) peptides into soluble oligomers and fibrils as a major underlying event in Alzheimer's disease (AD) pathogenesis. Herein, we employed amyloid-degrading keratinase (kerA) enzyme as a key A -binding scaffold to identify five keratinase-guided peptides (KgPs) capable of interacting with and altering amyloidogenic conversion of A The KgPs showed micromolar affinities with A and abolished its sigmoidal amyloidogenic transition, resulting in abrogation of fibrillogenesis. Comprehensive assessment using dynamic light scattering (DLS), atomic force microscopy (AFM) and Fourier-transform infrared (FTIR) spectroscopy showed that KgPs induced the formation of oligomers comparatively larger than the native A oligomers but with a significantly reduced cross- signature. These oligomers exhibited low immunoreactivity against oligomer-specific (A11) and fibril-specific (OC) antibodies and rescued neuronal cells from A oligomer toxicity as well as neuronal apoptosis. Structural analysis using molecular docking and molecular dynamics (MD) simulations showed two preferred KgP binding sites (Lys16-Phe20 and Leu28-Val39) on the NMR ensembles of monomeric and fibrillar A , indicating an interruption of crucial hydrophobic and aromatic interactions. Overall, our results demonstrate a new approach for designing potential anti-amyloid molecules that could pave way for developing effective therapeutics against AD and other amyloid diseases.