Developing Small-Molecule Regulators of the Hsp70/Hsp40 Complex

Abstract

Alzheimer’s Disease is a tauopathy, meaning that misfolded tau proteins aggregate in the extracellular matrix causing gradual neurodegeneration. Research has shown the chaperone protein Hsp 70 to be a key factor in the formation of protein aggregates that contribute to the pathology of the disease. Hsp 70 works in concert with Hsp 40 to regulate protein folding, refolding and degradation. Inhibition of Hsp 70 has been shown to decrease protein aggregates. Flavanoids such as myricetin have proven to be effective inhibitors of Hsp70 but very poor drug candidates. A molecular modeling program was used to create a list of myricetin-analogs that were then tested for inhibitory potential by the Malachite Green Assay, Quinaldine Red Assay and ELISA. All thirteen chosen analogs proved to be ineffective inhibitors of the Hsp 70/Hsp 40 complex, but provided valuable insight into the interaction between myricetin and Hsp 70. The previously proposed myricetin binding site was likely incorrect and further investigation into the inhibition mechanism is necessary.