Dendrimer Effects on Peptide and Protein Fibrillation

Abstract

Dendrimers are synthetic, symmetrically branched polymers that can be manufactured to a high degree of definition and therefore present themselves as monodisperse entities. Flexible and globular in shape and compartementalized into a partly inaccessible interior and a highly exposed surface, they offer numerous possibilities for interactions with and responses to biological macromolecules and biostructures including cell membranes and proteins. By way of their multiple functional surface groups, they allow the design of surfaces carrying a multitude of biological motifs and/or charges giving rise to quite significant biological and physico-chemical effects. Here we describe the surprising ability of dendrimers to interact with and perturb polypeptide conformations, particularly efficiently towards amyloid structures; that is, the structures of highly insoluble polypeptide aggregates involved in a range of serious and irreversibly progressive pathological conditions (protein-misfolding diseases). Interesting as this may be, the interaction of dendrimers with such generic peptidic aggregates also offers a new perspective on the molecular mechanisms governing assembly and disassembly of amyloid structures and thereby on determinants of protein and peptide folding. Despite the potent disaggregative nature of various dendrimers, they have variable effects on the stability of different proteins, suggesting that they do not act as generic denaturants, but rather exert their effects via specific interactions with individual parts of each protein.

PAMAM Dendrimers as Potential Agents against Fibrillation ofα‐Synuclein, a Parkinson's Disease‐Related Protein

“…[25] The TEM, in a complementary fashion to the TFTbinding assays, showed an increased inhibitory effect on fibrillation with increasing concentration and generation number of PAMAM dendrimers. These findings are consistent with previously published data, [14,[16][17][18]25,26] , suggesting that modulation of the surface charge of the protein or peptide by a dendrimer can play a crucial role in modifying their fibrillation potential. However, although PAMAM did not maintain a-synuclein in a soluble monomeric state, there was an obvious difference in the aggregation pattern when it is present, which is also seen from Figure 2C, is that aggregation of a-synuclein without PAMAM leads to a clear solution, whereas in the presence of PAMAM, an opaque precipitate is produced because of the formation of insoluble amorphous aggregates.…”

“…Dendrimers are reported to not only inhibit the fibrillation but also remove pre-existing PrP SC fibrils. [14] To investigate this possibility for a-synuclein, solutions of a-synuclein fibrils, pre-formed as described for in vitro a-synuclein fibril formation, were subjected to 10 À5 M PAMAM G4, G5 and G6 and subsequently studied by TEM, TFT-binding and CD spectroscopy. Fibrils incubated without PAMAM at 37 8C with shaking for 7 d, did not show morphological changes visible in the TEM, except for possibly slight fragmentation of the fibrils into shorter length elements (Figure 5a, cf.…”

“…Dendrimers have drawn great interest with their inclusion in potential therapeutic strategies for neurodegenerative disorders, due to their capability of removing preexisting infectious fibrils as well as inhibiting de novo fibrillation. [14,15] The design and fabrication of dendrimers with the presence of amino groups on the dendrimer surfaces is a necessity for the exhibition of an inhibitory effects on fibrillation. [16] The amino-terminated branched polymers, including dendrimers of polyamidoamine (PAMAM) and poly(propylene)imine (PPI), were found to eliminate PrP SC -the protease-resistant isoform of prion peptide from a scrapie-infected cultured neuroblastoma cell line -without adverse effects on cell viability.…”

Dendrimers destabilize proteins in a generation‐dependent manner involving electrostatic interactions

“…[1][2][3] The typical building block is polypropylene imine (PPI, usually with a diaminobutyrate core) or polyamino amine (PAMAM, with an ammonia or diaminoethanoate core). Regular branching leads to a globular structure where each new branching point (generation) provide an additional shell on the surface.…”

Phytosynthesis of gold nanoparticles using Mappia foetida leaves extract and their conjugation with folic acid for delivery of doxorubicin to cancer cells

“…This property is facilitated by attaching the drugs to the NPs and allows the use of lower doses of drugs, which are less toxic with improved therapeutic efficacy [20]. Furthermore, AuNPs displays remarkable conjugation capabilities due to their large surface area which allows them to bind various chemical compounds including drugs, proteins and other molecules by covalent bonds [21].…”