Chemical kinetics for drug discovery to combat protein aggregation diseases

• Protein misfolding diseases largely lack effective pharmaceutical treatments.
• Compounds with the ability to interfere with protein aggregation are attractive drug candidates.
• The search for inhibitors requires a detailed understanding of the inhibition mechanisms.
• Chemical kinetic analysis plays a key role in identifying the inhibition mechanisms.

Protein misfolding diseases are becoming increasingly prevalent, yet there are very few effective pharmacological treatments. The onset and progression of these diseases is associated with the aberrant aggregation of normally soluble proteins and peptides into amyloid fibrils. Because genetic and physiological findings suggest that protein aggregation is a key event in pathogenesis, an attractive therapeutic strategy against this class of disorders is the search for compounds able to interfere with this process, in particular by suppressing the formation of soluble toxic oligomeric aggregates. In this review, we discuss how chemical kinetics can contribute to the fundamental understanding of the molecular mechanism of aggregation, and speculate on the implications for the development of therapeutic molecules that inhibit specific steps in the aggregation pathway that are crucial for preventing toxicity.