Inhibiting Protein Aggregation by Small Molecule-Based Colloidal Nanoparticles

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 variety of colloidal nanoparticles can be designed either for inhibiting or disintegrating or clearing of protein aggregates. The Account ends with a Conclusions and Outlook section that discuss a vision for development of therapeutic nanodrug for protein aggregation-related diseases.

Automated summary

Protein aggregation is associated with various human diseases, and research is focused on understanding the mechanisms of protein aggregation, cytotoxicity of protein aggregates, and developing drugs for these diseases. Antiamyloidogenic materials such as small molecules and nanomaterials have shown potential in inhibiting protein aggregation and improving drug performance, but further improvements are needed for effective drug development strategies.