Peptide treatment of human plasma disrupts metabolic and age-related pathologies via heat shock protein 70

Aim: A seven amino acid cyclic peptide has been applied to human blood plasma treated with glucose metabolite methylglyoxal (MG) in “proof of concept” experiments to determine the peptide’s ability to counteract pathologies associated with hyperglycemia. Similar pathologies are evident during aging and in age-related disorders. In fact, elevated MG levels in the blood lead directly to diabetic complications and accelerated aging, including cognitive decline. These changes are attributed to oxidant stress and amyloidogenesis, the latter involving toxic accumulations of blood and tissue proteins. Methods: cSKE7 was redesigned from cell survival-promoting and anti-inflammatory fragments near the N-terminus of human/primate “orphan” protein DSEP/Dermcidin and incubated at low micromolar concentrations with the MG-stressed human plasma for 24 hours. The modified design of the new compound offers several practical advantages over predecessors including cyclic stability and a marked increase in aqueous solubility. Results: The peptide dispersed thioflavin-T-stained amyloid aggregates and reduced oxidant stress as measured by plasma levels of free thiols and of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Since these N-terminal fragments of DSEP/Dermcidin have been shown to bind and influence the activity of heat shock protein 70 (HSP70), HSP70 inhibitor pifithrin-μ was added to the plasma prior to peptide treatment. The inhibitor disrupted amyloid dispersion and both peptide-induced and, in some cases, normally occurring antioxidant effects, suggesting these reparative activities are HSP70 dependent. Conclusions: The results are discussed in terms of their potential use in new therapies for the complications of metabolic disease and disorders of aging that result from a deterioration of the quality control mechanisms of proteostasis.