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...
