Heptamer Peptide Disassembles Native Amyloid in Human Plasma Through Heat Shock Protein 70.

Proteostasis, which includes the repair and disposal of misfolded proteins, depends, in part, on the activity of heat shock proteins (HSPs), a well-known class of chaperone molecules. When this process fails, abnormally folded proteins may accumulate in cells, tissues, and blood. These species are a hallmark of protein aggregation diseases, but also amass during aging, often in the absence of an identified clinical disorder. We report that a neuroprotective cyclic heptapeptide, CHEC-7, which has been applied systemically as a therapeutic in animal neurodegeneration models, disrupts such aggregates and inhibits amyloidogenesis when added in nanomolar concentrations to human plasma. This effect includes aggregates of amyloid beta (Aβ1-40, 1-42), prominent features of Alzheimer's disease pathology. The activity of endogenous HSP70, a recently discovered target of the peptide, is required as demonstrated by both antibody blocking and application of pifithrin-μ, an HSP70 inhibitor. CHEC-7 is the first high-affinity compound to stimulate HSP70's disaggregase activity and therefore enable this endogenous mechanism in a human systemic environment, increasing the likelihood of a convenient therapy for protein aggregate disease, including age-related failures of protein repair.