Inhibitory effects of sesquiterpene lactones on the aggregation and cytotoxicity of prion neuropeptide

Abstract

The misfolding and conformational transformation of prion protein (PrP) are crucial to the progression of prion diseases. Screening for available natural inhibitors against prion proteins can contribute to the rational design and development of new anti-prion drugs and therapeutic strategies. The prion neuropeptide, PrP106-126 is commonly used as a model peptide of the abnormal PrPSc, and a number of potential inhibitors were explored against the amyloid fibril formation of PrP106-126. The well-known sesquiterpene lactone, artemisinin, shows diverse biological functions in anti-malarial, anti-cancer and lowering glucose. However, its inhibitory effect on PrP106-126 fibrillation is unclear. In this work, we selected two sesquiterpene lactones, artemisinin (1) and artesunate (2), to explore their roles in PrP106-126 aggregation by a series of physicochemical and biochemical methods. The results demonstrated that 1 and 2 could effectively impede the formation of amyloid fibrils and remodel the preformed fibrils. The binding of the small molecules to PrP106-126 was dominated by electrostatic, hydrophobic and hydrogen bonding interactions. In addition, both compounds exhibited neuroprotective effects by reducing peptide oligomerization. 2 showed better inhibition and regulation on peptide aggregation and cellular viability than 1 due to its specific succinate modification. Our study provides the information of sesquiterpene lactones to prevent PrP fibril formation and other related amyloidosis.