Nanochaperones Based on Hydrophobic Interaction and Coordination Inhibit Protein Misfolding and Fibrillation

Abstract

Amyloidosis is characterized by the deposition of fibrillar aggregates, with a specific peptide or protein as the primary component, in affected tissues or organs. Excessive proliferation and deposition of amyloid fibrils can cause organismal dysfunction and lethal pathological outcomes associated with amyloidosis. In this study, a nanochaperone (nChap-NA) was developed to inhibit protein misfolding and fibrillation by simulating the function of natural molecular chaperones. The nanochaperone was prepared by self-assembly of two block copolymers PEG-b-PCL and PCL-b-P(NIPAM-co-AANTA), which had a phase-separated surface consisting of hydrophobic PNIPAM microdomains with coordinative NTA(Zn) moieties and hydrophilic PEG chains. The hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn) synergistically work together to effectively trap the amyloid monomer and block its fibrillation site. Insulin and human islet amyloid polypeptide (hIAPP) were used as model proteins to investigate the nanochaperone’s inhibition of amyloid misfolding and fibrillation. It was proved that the nanochaperone could stabilize the natural conformation of the trapped insulin and hIAPP, and effectively inhibit their fibrillation. In vivo study demonstrated that the nanochaperone could effectively preserve the bioactivity of insulin and reduce the cytotoxicity caused by hIAPP aggregation. This study may provide a promising strategy for the prophylactic treatment of amyloidosis.