Multivalent interacting glycodendrimer to prevent amyloid-peptide fibril formation induced by Cu(II): A multidisciplinary approach

Janaszewska, Anna; Klajnert‐Maculewicz, Barbara; Marcinkowska, Monika; Duchnowicz, Piotr; Appelhans, Dietmar; Grasso, Gianvito; Deriu, Marco Agostino; Danani, Andrea; Cangiotti, Michela; Ottaviani, M. Francesca

doi:10.1007/s12274-017-1734-9

Cited by 26 publications

(21 citation statements)

References 91 publications

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“…Noteworthy, this relationship can hardly be inferred only by biological in vitro and in vivo experiments due to the high number of variables and complexity of the investigated biological system. In this context, a coupled approach based on experimental and computational modelling may provide fruitful information on molecular mechanisms driving interactions of ligand-target systems [40][41][42] , such as a polymer-siRNA complexes 15,33,34,[41][42][43] .…”

Section: Introductionmentioning

confidence: 99%

Elucidating the role of surface chemistry on cationic phosphorus dendrimer–siRNA complexation

et al. 2018

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In the field of dendrimers targeting small interfering RNA (siRNA) delivery, dendrimer structural properties, such as the flexibility/rigidity ratio, play a crucial role in the efficiency of complexation. However, advances in organic chemistry have enabled the development of dendrimers that differ only by a single atom on their surface terminals. This is the case for cationic phosphorus dendrimers functionalized with either pyrrolidinium (DP) or morpholinium (DM) terminal groups. This small change was shown to strongly affect the dendrimer-siRNA complexation, leading to more efficient anti-inflammatory effects in the case of DP. Reasons for this different behavior can hardly be inferred only by biological in vitro and in vivo experiments due to the high number of variables and complexity of the investigated biological system. However, an understanding of how small chemical surface changes may completely modify the overall dendrimer-siRNA complexation is a significant breakthrough towards the design of efficient dendrimers for nucleic acid delivery. Herein, we present experimental and computational approaches based on isothermal titration calorimetry and molecular dynamics simulations to elucidate the molecular reasons behind different efficiencies and activities of DP and DM. Results of the present research highlight how chemical surface modifications may drive the overall dendrimer-siRNA affinity by influencing enthalpic and entropic contributions of binding free energy. Moreover, this study elucidates molecular reasons related to complexation stoichiometry that may be crucial in determining the dendrimer complexation efficiency.

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Section: Introductionmentioning

confidence: 99%

Elucidating the role of surface chemistry on cationic phosphorus dendrimer–siRNA complexation

et al. 2018

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“…The previously highlighted conformational instability of residues V24 and G37 in the U-shaped model can be explained by analysing the secondary structure probability of the two simulated systems ( Figure 1 c). For each model the secondary structure has been calculated as a probability along all chains and all considered frames, as done in previous works [ 27 ]. The secondary structure probability along the REMD ensemble at 300 K ( Figure 1 c, lower row) was compared with the same probability in the PDB model ( Figure 1 c, upper row) for both U-shaped ( Figure 1 c, left) and S-shaped ( Figure 1 c, right) architectures.…”

Section: Resultsmentioning

confidence: 99%

“…Computational approaches such as Replica Exchange Molecular Dynamics (REMD) can be used as a powerful tool to elucidate the molecular mechanisms responsible for protein hierarchical organization. In fact, computer simulations have been widely demonstrated to be helpful in capturing mechanisms of protein folding [ 24 , 25 , 26 ] and protein-protein aggregation [ 27 , 28 ]. Recent computational works investigated the stability of the U-Shaped fibril models of Aβ 1–42 and Aβ 1–40 species [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies

Grasso

Rebella

Muscat

et al. 2018

IJMS

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Alzheimer’s disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ1–40 and Aβ1–42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ1–40 peptides can only assume U-shaped conformations while Aβ1–42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aβ17–42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils.

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“…[15] In this sense, dendrimerso rd endritic systems, due to their unique properties, such as their monodisperse structure and high multifunctionalizationc apacity,h ave provedt ob ei deal systems. [16] There are several dendritic systemso fd ifferentt opologies,s uch as polyamidoamine (PAMAM), [17] glycodendrimer, [18] phosphorus, [19] and carbosilane, [20] that are being studied in the treatment of diseases associated with protein accumulationa nd have been shown to be effective in preventing the bad folding of proteins.F or example, low-generation anionic dendrimers or OH-terminatedP AMAM dendrimers have the capacity to modulate the self-assembly of IAPP,a ccelerating or preventing its accumulation. [21] In addition, cationic poly(propyleneimine) dendrimers functionalized with maltose reduce amyloid cytotoxicity in PC12 and SH-SY5Yc ells.…”

Section: Introductionmentioning

confidence: 99%

Cationic Carbosilane Dendritic Systems as Promising Anti‐Amyloid Agents in Type 2 Diabetes

Lozano-Cruz

Alcarraz-Vizán

Mata

et al. 2020

Chemistry A European J

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The most common denominator of many of the neurodegenerative diseases is badly folded protein accumulation, which results in the formation of insoluble protein deposits located in different parts of the organism, causing cell death and tissue degeneration. Dendritic systems have turned out to be a promising new therapeutic approach for the treatment of these diseases due to their ability to modulate the folding of these proteins. With this perspective, and focused on type 2 diabetes (T2D), characterized by the presence of deposits containing the amyloidogenic islet amyloid polypeptide (IAPP), we demonstrate how different topologies of cationic carbosilane dendrimers inhibit the formation of insoluble protein deposits in pancreatic islets isolated from transgenic Tg‐hIAPP mice. Also, the results obtained by the modification of dendritic carbosilane wedges with the chemical chaperone 4‐phenylbutyric acid (4‐PBA) at the focal point confirmed their potential as anti‐amyloid agents with a concentration efficiency in their therapeutic action five orders of magnitude lower than that observed for free 4‐PBA. Computational studies, which determined the main interaction between IAPP and dendrimers at the atomic level, support the experimental work.

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Multivalent interacting glycodendrimer to prevent amyloid-peptide fibril formation induced by Cu(II): A multidisciplinary approach

Cited by 26 publications

References 91 publications

Elucidating the role of surface chemistry on cationic phosphorus dendrimer–siRNA complexation

Elucidating the role of surface chemistry on cationic phosphorus dendrimer–siRNA complexation

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies

Cationic Carbosilane Dendritic Systems as Promising Anti‐Amyloid Agents in Type 2 Diabetes

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