Hydrophobic Modification of Carboxyl-Terminated Polyamidoamine Dendrimer Surface Creates a Potent Inhibitor of Amyloid-β Fibrillation

Abstract

Amyloid β-peptide (Aβ) fibrillogenesis is a major hallmark of Alzheimer's disease (AD); inhibition of Aβ fibrillation is thus considered as a promising strategy for AD prevention and treatment. Our group has previously proposed the hydrophobic binding-electrostatic repulsion (HyBER) hypothesis, which provides guidance for the design of new amyloid inhibitors. Inspired by the HyBER hypothesis, we have herein proposed to synthesize hydrophobic-modified generation 5 carboxyl-terminated polyamidoamine dendrimer, denoted as PAMP, to create a potent inhibitor with a negatively charged hydrophobic surface. Results indicate that the PAMP with a proper degree of phenyl substitution (30−42%) alters the conformation of Aβ 42 through both hydrophobic binding and electrostatic repulsive forces on its surface. With these well-balanced interactions, the inhibitor can even completely inhibit the formation of β-sheet structure of the peptide, accompanied by changes at the level of the fibrillary architecture. Moreover, the results also indicate that changes of Aβ 42 aggregation pathway influenced by the PAMP occur at the very early stage, so the PAMP can significantly avoid the formation of toxic intermediates of Aβ 42 aggregation.

Carbosilane Dendron–Peptide Nanoconjugates as Antimicrobial Agents

“…Connections between peptide ability to aggregate bacteria and oligomerization ability of these peptides themselves were already described. , From this point of view, the disaggregation property of studied dendrons at the bacterial level might be justified by the same property at the peptide level. This ability of some dendrimers with respect to peptides was already described, for example, in some “dendrimer–amyloid” studies. , Computer modeling of a small AMP3 cluster indicates the ability of this positively charged peptide to create oligomers (Figure S17) and this ability is likely to be enhanced near the negatively charged surface of the bacterium.…”

Mixed Carboxyl and Hydrophobic Dendrimer Surface Inhibits Amyloid-β Fibrillation: New Insight from the Generation Number Effect

“…As shown in Figure S1, low generations of dendrimers have a flattened and asymmetric shape, while the structure becomes globular and possesses empty hydrophobic cavities inside for the high-generation dendrimers. − The diverse structures of PAMAM offer abundant base materials for further study of the HyBER theory. According to our previous study, comparison under the same ratio of phenyl groups to the negatively charged groups would be reasonable. Thus, in this research, we use G3, G4, G5, and G6 PAMAMs as base materials to synthesize phenyl-derivatized dendrimers of different generations with DS of hydrophobic groups around 30% and then study their effect on inhibiting Aβ 42 fibrillation.…”

“…Polyamidoamine (PAMAM), one of the most well-known dendrimers, has been widely investigated in biomedical applications, for example, gene therapy, drug delivery, and magnetic resonance imaging. − Carboxyl-terminated polyamidoamine dendrimer (PAMAM) is a kind of biocompatible nanomaterial with only carboxyl groups on its surface, − which offers a perfect base material for the design of Aβ inhibitors based on the HyBER theory. In the previous study, we did this by synthesizing a series of phenyl-derivatized generation 5 carboxyl-terminated PAMAM (G5) to get potent amyloid inhibitors with a negatively charged hydrophobic surface that meets the HyBER theory on inhibiting Aβ fibrillogenesis. The results demonstrated the design and indicated that the ratio of hydrophobic groups to the negatively charged groups is vital, and only dendrimers with proper degrees of substitution (DS > 30%) of hydrophobic groups can achieve the favorable inhibition effect.…”

Bioinspired synthetic polymers-based inhibitors of Alzheimer's amyloid-β peptide aggregation

“…103 Highly multivalent polymers, such as dendrimers, are another type of polymeric material examined as potential agents for neurodegenerative disorders, such as poly(amidoamine) PAMAM dendrimers which retarded the aggregation of Aβ fragments at higher concentrations. 34,104,105 In this section, various examples of polymeric Aβ-inhibitors such as polymeric nanoparticles, polymer-based micelles, polymer-peptide conjugates, conjugated polymers and glycopolymers are discussed (as shown in Fig. 2).…”