"Janus" cyclic peptides: a new approach to amyloid fibril inhibition?

ABSTRACT: Cyclic peptides are increasingly being shown as powerful inhibitors of fibril formation, and have the potential to be therapeutic agents for combating many debilitating amyloid-related diseases. One such example is a cyclic peptide derivative from the human apolipoprotein C-II, which has the ability to inhibit fibril formation by the fibrillogenic peptide apoC-II(60-70). Using classical molecular dynamics and electronic structure calculations, we were able to provide insight into the interaction between the amyloidogenic peptide apoC-II(60-70) and its cyclic derivative, cyc(60-70). Our results showed that cyc(60-70) induced increased flexibility in apoC-II(60-70), suggesting that one mechanism by which cyc(60-70) inhibits fibrillisation is by destabilising apoC-II(60-70) structure, rendering it incapable of adopting fibril favouring conformations. In contrast, cyc(60-70) shows less flexibility upon binding to apoC-II(60-70), which is predominantly mediated by hydrophobic interactions between the aromatic rings of the peptides. This effectively creates a cap around the fibril-forming region of apoC-II(60-70) and generates an outer hydrophilic shell that discourages further apoC-II(60-70) peptide self-association. We showed that apoC-II(60-70) exhibited stronger binding affinity for the hydrophobic face of cyc(60-70) and weakest binding affinity for the hydrophilic side. This suggests that cyc(60-70) can be an effective fibril inhibitor due to its amphipathic character, like that of the "Janus"-type particles. This property can be exploited in the design of specific inhibitors of amyloid fibril formation.

SUBMITTER: Todorova N 

PROVIDER: S-EPMC3577749 | biostudies-other | 2013

REPOSITORIES: biostudies-other