Inhibiting Protein Aggregation by Small Molecule-Based Colloidal Nanoparticles

Abstract

Conspectus Protein aggregation is associated with different human diseases such as Alzheimer’s, Huntington’s, Parkinson’s, diabetes type II, and cataracts. Currently no effective treatment exists for many of these diseases, particularly for neurological disorders. Ongoing research focuses on understanding the origin of protein aggregation, nucleation–growth mechanism of protein aggregation, origin of cytotoxicity of protein aggregates, cellular response of toxic protein aggregates, progress of diseases at intra/extracellular space, and drug developments for respective diseases. Key issues are the identification of molecular drugs that can inhibit protein aggregation at early stage, lowering of toxicity due to protein aggregates, delivery of drugs to remote organ and intracellular space, clearing matured protein aggregates from cell/extracellular space/brain, and design of effective therapeutic strategy. Chemists and materials scientists have identified a wide variety of anti­amyloidogenic small molecules, macromolecules, and nanomaterials. It is shown that anti­amyloidogenic molecules prevent protein oligomerization via binding to protein, masking metal ions (via chelating with metal ions) that are responsible for protein aggregation via generating reactive oxygen species (ROS), and lowering protein–protein interaction via macromolecular crowding effect. Similarly, nanoscale materials with curved surface and multiple chemical functional groups act as adsorption/binding sites of proteins, modulate nucleation–growth kinetics of protein aggregation, and delay/inhibit protein aggregation in many cases. However, performance of all these anti­amyloidogenic materials needs significant improvement, and proper therapeutic strategies are required for effective drug development. In this Account, we describe that the performance of anti­amyloidogenic molecules can be greatly improved via appropriate design into colloidal and nanoparticle form. We first discuss different human diseases that are linked with protein aggregation, location and mechanism of protein aggregation, adverse effect of protein aggregates on cell functions, and progress of different diseases due to these effects. Next, we discuss different classes of anti­amyloidogenic materials, their mechanism of inhibiting protein aggregation, and existing approaches for their utilization under in vitro/in vivo conditions. Further, we show that anti­amyloidogenic performance of small molecules can be enhanced as high as 100 000-times if they are transformed into appropriately designed colloidal nanoparticles. In particular, we explain that such enhanced performance is due to increased bioavailability at intra/extracellular space, modular binding property with protein, and higher brain delivery option in nanoparticle form. Next, we discuss different strategies for the preparation of colloidal nanoparticle where anti­amyloidogenic molecules are terminated or loaded with nanoparticle and polymer micelle and their mechanism of action. Finally, we discuss that a wide variet...

Antiglycation potential of plant based TiO2 nanoparticle in D‐ribose glycated BSA in vitro

“…The development and accumulation of amyloidogenic proteins and lipoproteins correlated with the pathological events in neurodegenerative diseases, diabetes and related complications. As per the observations from this result, TNP inhibits the mechanism by which the confirmation of proteins got altered at the same time TNP also prevents the proteins from being getting aggregated under the influence of AGEs, especially with the glycation specific amino acids that is, arginine and lysine 44,45 …”

“…As per the observations from this result, TNP inhibits the mechanism by which the confirmation of proteins got altered at the same time TNP also prevents the proteins from being getting aggregated under the influence of AGEs, especially with the glycation specific amino acids that is, arginine and lysine. 44,45 3.9 | Prevention of AGEs formation by TNP…”

Functional Bacterial Amyloids: Understanding Fibrillation, Regulating Biofilm Fibril Formation and Organizing Surface Assemblies

“…In vitro studies have identified numerous potential alternatives to polyphenols for inhibiting amyloid formation based on in vitro studies [124][125][126], but their use in vivo is a challenge. Fortunately, there is a growing number of studies highlighting the loading of small molecules into nanoparticles, such as lipid vesicles or polymer-coated albumin aggregates [127][128][129][130][131]. This packaging improves the ability to cross the blood-brain barrier (for therapy) or penetrate biofilm (to combat functional amyloid), allowing the small molecules to target amyloidogenic monomers.…”

Synthesis and Application of Trehalose Materials

“…Trehalose has been found to be effective in the treatment of different neurodegenerative pathologies including Alzheimer’s, Parkinson’s, and Huntington’s diseases. , Although the exact mechanism is not clear yet, it likely includes antiaggregation, anti-inflammation, and, in particular, autophagy induction, that is, the intracellular removal or destruction of unnecessary or dysfunctional components . Trehalose glycoclusters and nanocarriers were more efficient in delaying fibril formation and protein aggregation and protecting neurons than the small molecule trehalose, indicating that the cluster effect seen in stabilizing proteins with trehalose polymers is also applicable. Recently, poly­(trehalose) was also found to be effective in preventing Aβ peptide aggregation, part of the progression of Alzheimer’s disease.…”

“…As a small molecule, trehalose is a highly effective stabilizer and has been incorporated into polymers and other polymeric materials for even more dramatic stabilization results. 19 − 23 As our group has previously shown, in heat and lyophilization stability assays, proteins retain greater bioactivity in the presence of trehalose polymers (excipient, conjugate, hydrogel, or nanogel) than alone or with the same weight concentration of trehalose. 19 , 20 , 24 In the same vein, trehalose nanoparticles were better than trehalose alone at preventing proteins from undergoing fibrillation.…”