Designing de Novo Small Molecules That Control Heat Shock Protein 70 (Hsp70) and Heat Shock Organizing Protein (HOP) within the Chaperone Protein-Folding Machinery

Protein–protein
interactions (PPIs) regulate all signaling
pathways for cellular function. Developing molecules that modulate
PPIs through the interface of their protein surfaces has been a significant
challenge and there has been little success controlling PPIs through
standard molecular library screening approaches. PPIs control the
cell’s protein-folding machinery, and this machinery relies
on a multiprotein complex formed with heat shock protein 70 (Hsp70).
Described is the design, synthesis, and biological evaluation of molecules
aimed to regulate the interaction between two proteins that are critical
to the protein-folding machinery: heat shock protein 70 (Hsp70) and
cochaperone heat shock organizing protein (HOP). We report the first
class of compounds that directly regulate these two protein–protein interactions and inhibit
protein folding events.