Dataset Information

Nanomedicine Against A? Aggregation by ?-Sheet Breaker Peptide Delivery: In Vitro Evidence.

ABSTRACT: The accumulation of amyloid ? (A?) triggers a cascade of toxic events in Alzheimer's disease (AD). The KLVFF peptide can interfere with A? aggregation. However, the peptide suffers from poor bioavailability and the inability to cross the blood-brain barrier. In this work, we study the possibility of adopting nanomedicine to overcome KLVFF limits in biodistribution. We produced new engineered polymeric nanoparticles (NPs), and we evaluated the cellular toxicity of these NPs and validated that KVLFF peptides released by NPs show the same promising effects on AD pathology. Our results revealed the successful generation of KVLFF loaded NPs that, without significant effects on cell heath, are even more potent in reversing A?-induced pathologies compared to the free peptide. Therefore, NPs will significantly advance KVLFF treatment as a therapeutic option for AD.

SUBMITTER: Pederzoli F

PROVIDER: S-EPMC6920811 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Nanomedicine Against Aβ Aggregation by β-Sheet Breaker Peptide Delivery: In Vitro Evidence.

Pederzoli Francesca F Ruozi Barbara B Duskey Jason J Hagmeyer Simone S Sauer Ann Katrin AK Grabrucker Stefanie S Coelho Romina R Oddone Natalia N Ottonelli Ilaria I Daini Eleonora E Zoli Michele M Vandelli Maria Angela MA Tosi Giovanni G Grabrucker Andreas M AM

Pharmaceutics 20191101 11

The accumulation of amyloid β (Aβ) triggers a cascade of toxic events in Alzheimer's disease (AD). The KLVFF peptide can interfere with Aβ aggregation. However, the peptide suffers from poor bioavailability and the inability to cross the blood-brain barrier. In this work, we study the possibility of adopting nanomedicine to overcome KLVFF limits in biodistribution. We produced new engineered polymeric nanoparticles (NPs), and we evaluated the cellular toxicity of these NPs and validated that KVL ...[more]

PMID: 31683907

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Project description:Alzheimer's disease is characterized by amyloid-β aggregation. Currently, all the approved medications are to treat the symptoms but there is no clinically approved treatment for the cure or to prevent the progression of Alzheimer's disease (AD). Earlier reports suggest the use of small molecules and peptides to target and destabilize the amyloid fibril. The use of Beta Sheet Breaker (BSB) peptides seems to be a promising and attractive therapeutic approach as it can strongly bind and destabilize the preformed amyloid fibril. There are experimental studies describing the destabilization role of various BSB peptides, but the exact mechanism remains elusive. In the current work, an attempt is made to study the destabilization mechanism of different BSB peptides on preformed amyloid protofibril using molecular docking and simulations. Molecular docking of eight different BSB peptides of varying length (5-mer to 10-mer) on the Abeta protofibril was done. Docking was followed by multiple sets of molecular simulations for the Abeta protofibril-BSB peptide complex for each of the top ranked poses of the eight BSB peptides. As a control, multiple sets of simulations for the Abeta protofibril (APO) were also carried out. An increase in the RMSD, decrease in the number of interchain hydrogen bonds, destabilization of important salt bridge interactions (D23-K28), and destabilization of interchain hydrophobic interactions suggested the destabilization of Abeta protofibril by BSB peptides. The MM-GBSA free energy of binding for each of the BSB peptides was calculated to measure the binding affinity of BSB peptides to Abeta protofibril. Further residue wise contribution of free energy of binding was also calculated. The study showed that 7-mer peptides tend to bind strongly to Abeta protofibril as compared to other BSB peptides. The KKLVFFA peptide showed better destabilization potential as compared to the other BSB peptides. The details about the destabilization mechanism of BSB peptides will help in the design of other peptides for the therapeutic intervention for AD.

Dataset Information

Nanomedicine Against A? Aggregation by ?-Sheet Breaker Peptide Delivery: In Vitro Evidence.

Publications

Nanomedicine Against Aβ Aggregation by β-Sheet Breaker Peptide Delivery: In Vitro Evidence.

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