"Janus" cyclic peptides: a new approach to amyloid fibril inhibition?
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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3577749?pdf=render |
| _version_ | 1819149062427901952 |
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| author | Nevena Todorova Levi Yeung Andrew Hung Irene Yarovsky |
| author_facet | Nevena Todorova Levi Yeung Andrew Hung Irene Yarovsky |
| author_sort | Nevena Todorova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T13:55:38Z |
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| id | doaj.art-b6f7269cbf194351acee2b1a35a2d107 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T13:55:38Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b6f7269cbf194351acee2b1a35a2d1072022-12-21T18:23:34ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0182e5743710.1371/journal.pone.0057437"Janus" cyclic peptides: a new approach to amyloid fibril inhibition?Nevena TodorovaLevi YeungAndrew HungIrene YarovskyCyclic 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.http://europepmc.org/articles/PMC3577749?pdf=render |
| spellingShingle | Nevena Todorova Levi Yeung Andrew Hung Irene Yarovsky "Janus" cyclic peptides: a new approach to amyloid fibril inhibition? PLoS ONE |
| title | "Janus" cyclic peptides: a new approach to amyloid fibril inhibition? |
| title_full | "Janus" cyclic peptides: a new approach to amyloid fibril inhibition? |
| title_fullStr | "Janus" cyclic peptides: a new approach to amyloid fibril inhibition? |
| title_full_unstemmed | "Janus" cyclic peptides: a new approach to amyloid fibril inhibition? |
| title_short | "Janus" cyclic peptides: a new approach to amyloid fibril inhibition? |
| title_sort | janus cyclic peptides a new approach to amyloid fibril inhibition |
| url | http://europepmc.org/articles/PMC3577749?pdf=render |
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