A smart adaptable metal sequestering peptide conjugate to modulate Aβ fibrillar aggregation.

Abstract

The aggregation of amyloid β peptide (Aβ) in the presence of elevated levels of transition-metal ions, e.g., Fe3+, Cu2+, Zn2+, is accountable for enhanced cellular toxicity in Alzheimer's disease. Many strategies are reported to inhibit either Cu2+, Zn2+, or Fe3+-induced Aβ fibrillation, focused on one metal. Herein, a taurine-containing adaptable metal sequestering peptide (AMSP) has been developed as the modulator of any of the cited metal-induced Aβ-aggregation in vitro. We designed the peptide conjugate comprising VFFA as a recognition motif and a taurine moiety coupled with a pendant chain of glutamic acid such that the -SO3H groups of taurine lie nearby 13His and 14His of Aβ, and sequester such metal ions that construct the salt bridge preponderantly via13His-metal-14His composition as well as bridges with 6His of Aβ. We checked the modulation of fibrillar aggregates of Aβ in the presence of metal ions by monitoring the fibril accumulation using several biophysical methods. The results established that non-aggregating AMSP sequesters Zn2+ preferably, along with Fe3+ and Cu2+ ions from the metal-Aβ complex at the physiological condition, efficiently inhibiting Aβ aggregation. While such adaptable metal binders that can chelate various metals are new, AMSP inhibits aggregation through selective recognition and metal scavenging.