Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation

Abstract

Many globular and natively disordered proteins can convert into amyloid fibers. These fibers are associated with numerous pathologies1 as well as with normal cellular functions2,3, and frequently form during protein denaturation4,5. Inhibitors of pathological amyloid fibers could serve as leads for therapeutics, provided the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibers as templates, we have designed and characterized an all D-amino acid inhibitor of fibrillation of the tau protein found in Alzheimer’s disease, and a non-natural L-amino acid inhibitor of an amyloid fiber that enhances sexual transmission of HIV. Our results indicate that peptides from structure-based designs can disrupt the fibrillation of full-length proteins, including those like tau that lack fully ordered native structures.

Rational design of potent domain antibody inhibitors of amyloid fibril assembly

“…Our work is inspired by previous studies that demonstrated the ability of amyloidogenic peptide fragments to inhibit fibrillization of polypeptides containing the cognate peptide sequences (25)(26)(27)(28)(29)(30)(31). A common concern when using amyloidogenic peptides as aggregation inhibitors is their poor solubility.…”

Stepwise Organization of the β-Structure Identifies Key Regions Essential for the Propagation and Cytotoxicity of Insulin Amyloid Fibrils

“…By identifying such peptide segments, a novel amylome analysis has recently been developed to predict the amyloidogenicity of proteins (50). The deep involvement of the steric zipper structure in the self-propagating ability has been supported by the inhibition of insulin fibrillation by an octapeptide coding amino acid sequence that forms a steric zipper (LVEALYLV) (51) and the effectiveness of the structure-based design of the peptide inhibitors of amyloid fibril formation for favorable affinity with the steric-zipper structure (52). Regarding the structural basis of cytotoxicity, the steric zipper structure is also more likely to intrude into biomembranes, resulting in cellular dysfunction, although the detailed roles of the steric zipper structure have not yet been elucidated.…”

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…One recent example is the design of a capping peptide blocking the elongation of PHFs (Sievers et al 2011).…”