Schlüsselwörter
(Englisch)
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Dendrimers; Copper; beta-Amyloid; Prions; Neurodegenerative diseases; Molecular Dynamics; DFT;
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Forschungsprogramme
(Englisch)
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COST-Action TD0802 - Dendrimers in Biomedical Applications
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Kurzbeschreibung
(Englisch)
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Alzheimer's disease (AD) is one of the most common form of dementia. In 2006, there were 26.6 million sufferers world-wide, 10% of people over 65 years of age and 50% of those over 85 years of age have AD, which is predicted to affect more than 1% of population globally by 2050. It is recognized that AD is due to the deposition of fibrillar protein aggregates and gives rise to amyloid fibrils with shared structural features and properties. Currently used treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are as yet available. The main idea of this project is to improve existing therapies, and to develop new therapeutic tools where none exist, by employing so-called dendrimers. Dendrimers are a new class of polymeric materials with a well-defined structure and they have shown to be the first compounds that not only have the ability to inhibit fibril formation but also disrupt aggregates. In this project, we plan to study the interactions of beta-amyloid peptides/fibrils with several types of dendrimers (e.g. amido-amine, PPI or carbosilane based ones ) applying computer atomistic and coarse-grained simulations. The main focus will be on their performance in inhibition of fibrillogenesis and eventual disruption of already existing beta-amyloid fibrils/plaques . Through the combination of sophisticated computational and experimental techniques, thanks to confirmed partnerships, it will be possible to have a synergic approach which would provide valuable contribution in identification and optimization of the best dendrimer candidates for this promising type of AD therapy.
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Weitere Hinweise und Angaben
(Englisch)
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Full name of research-institution/enterprise: SUPSI Scuola Universitaria Professionale della Svizzera Italiana Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA) Università della Svizzera Italiana
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Partner und Internationale Organisationen
(Englisch)
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BG, CH, CZ, DE, DK, EL, ES, FI, FR, IE, IL, IT, LT, NL, NO, PL, PT, RO, SE, TR, UK
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Abstract
(Englisch)
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The project relates to the computational study of the interactions between some classes of dendrimers, beta- amyloids and ions. Many experiments indicate that dendrimers have in-vitro anti-fibrillation effect under particular conditions. To better understand the problem, interactions between Abeta40 and maltose decorated poly(propylene imine) dendrimers (mal-PPI) of generation 4 and 5 were studied under neutral and low pH conditions. The simulations of dendrimer/peptide systems confirmed favourable interactions between dendrimers and peptides which are rather electrostatically driven in case of cationic dendrimers and hydrogen-bond based in case of neutral maltose modified PPI dendrimers while combined electrostatic, h-bond and hydrophobic interactions seems to play a role in case of the SO3-mal-PPI anionic dendrimer. The results also support the hypothesis about heparin role in Abeta -peptide fibrillation and the possibility to use cationic dendrimers for heparin removal (neutralization) from the solution. Similarly like in case of beta-Amyloid cases, some types of dendrimers are also studied as anti-prionic agents: they reduce the level of protease resistant PrPSc in a prion strain-dependent manner. This led to the formulation of a new working model for dendrimer/prion interactions which proposes that dendrimers eliminate PrPSc by destabilizing the protein and rendering it susceptible to proteolysis. Some computational results in this project were published together with the experimental work (Biomacromolecules 2013, 14, 27-37). We also explored the interactions of dendrimers with specific cations (Cu++, Zn++) whose role in Alzheimer disease has been recently proved. These ions affect the fibrillation process but also seem to interfere with the functionality of natural A? peptide 'regulators'. Since some kinds of dendrimers may modulate the aggregation dynamics of the amyloid peptides, avoiding the mutual interactions in their free form, we performed a computational study about the interaction between ions and dendrimers. The complex dendrimer architecture can offer a big number of low affinity binding sites that can be relevant in several biological processes related to neurodegenerative diseases. In particular, we used a model of PPI dendrimer to study the local organization of groups able to coordinate Cu2+ ions, depending on surface decoration, generation and ion concentration. We found the possible structures of PPI-G4 bound to a single Cu2+ ion and the extent of distortion of the Cu-binding when the PPI-G4 dendrimer is decorated with maltose. In summary, this project used molecular modeling techniques to have a different insight about the molecular mechanisms behind the interactions between amyloids, ions and dendrimers, which proved to be potential aggregation inhibitors. We could study 1-to-1 interactions between the main actors. We did also an agreement with Universities of Lodz and Urbino to perform parallel experimental investigation (biological assays and EPR) related to interactions of the different dendrimers with both amyloid peptides and ions and further work will be devoted to a deeper study of the study the ionic competition with the three structures interacting all together. We did also an agreement with University of Lodz and University of Urbino to perform parallel experimental investigation (biological assay, EPR) related to interactions of the different dendrimers with both amyloid peptides and ions. We hope that our computational study combined with these experimental ones will bring interesting and valuable results. In summary, this project used molecular modeling techniques to have a different insight about the molecular mechanisms behind the interactions between amyloids, ions and dendrimers, which proved to be potential aggregation inhibitors. We could study one to one interactions between the main actors, and further work will be devoted to study the ionic competition with the three structures interacting all together.
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Datenbankreferenzen
(Englisch)
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Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. +41 31 322 74 82 Swiss Project-Number: C10.0146
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