Modulating Transthyretin Fibril Stability with D-Retro-Inverso Peptides

Abstract A major cause of heart failure in elderly patients is the deposition of transthyretin (TTR) fibrils. Using molecular dynamics simulations, we explore how the stability of TTR fibrils can be modulated by D-retro-inverso (DRI) peptides, built from D-amino acids with the sequence of the parent peptide switched. We screened a library of peptide candidates generated from aggregation-prone regions in the TTR sequence, including peptides from WALTZ-DB 2.0 database of amyloid peptides, and selected three peptides based on their potential to disrupt interactions in a structurally flexible region of the fibril. Peptides were docked to the surface of the TTR fibril using HADDOCK 2.4, followed by all-atom molecular dynamics simulations to evaluate peptide–fibril interactions and their effects on fibril structure. We finally describe a potential mechanism by which one of these peptides, DRI-K6V, perturbs the structural integrity of TTR fibrils, and identify the segment K80-S100 as a potential target for modulating TTR fibril stability. Our results may open the way to the design of peptide drugs targeting established TTR amyloidosis.