Volatile Anesthetic Sevoflurane Precursor 1,1,1,3,3,3-Hexafluoro-2-Propanol (HFIP) Exerts an Anti-Prion Activity in Prion-Infected Culture Cells

Takuto Shimizu,Takuto Shimizu,Emiko Nogami,Naomi Hachiya,Tadashi Yamashita,Yuka Ito,Kazuo Morikawa,Tsuyoshi Ogawa,Hisashi Yagi,Masaki Nagane,Fuyuki Kametani

doi:10.1007/s11064-021-03344-8

Abstract

Prion disease is a neurodegenerative disorder with progressive neurologic symptoms and accelerated cognitive decline. The causative protein of prion disease is the prion protein (PrP), and structural transition of PrP from the normal helix rich form (PrPC) to the abnormal β-sheet rich form (PrPSc) occurs in prion disease. While so far numerous therapeutic agents for prion diseases have been developed, none of them are still useful. A fluorinated alcohol, hexafluoro isopropanol (HFIP), is a precursor to the inhalational anesthetic sevoflurane and its metabolites. HFIP is also known as a robust α-helix inducer and is widely used as a solvent for highly aggregated peptides. Here we show that the α-helix-inducing activity of HFIP caused the conformational transformation of the fibrous structure of PrP into amorphous aggregates in vitro. HFIP added to the ScN2a cell medium, which continuously expresses PrPSc, reduced PrPSc protease resistance after 24-h incubation. It was also clarified that ScN2a cells are more susceptible to HFIP than any of the cells being compared. Based on these findings, HFIP is expected to develop as a therapeutic agent for prion disease.

Highlights

Prions are infectious pathogens that cause fatal neurodegenerative diseases by altering the three-dimensional structure of the causative protein by yet unknown mechanism
We explored the possibility of hexafluoro isopropanol (HFIP) as a therapeutic drug for prion diseases using recombinant prion protein (PrP) and scrapie-infected mouse neuroblastoma cells, an established in vitro model of prion disease
The effect of HFIP to PrP fibrils produced by the recombinant PrP was observed using transmission electron microscopy (TEM)

Summary

Introduction

Prions are infectious pathogens that cause fatal neurodegenerative diseases by altering the three-dimensional structure of the causative protein by yet unknown mechanism. We explored the possibility of HFIP as a therapeutic drug for prion diseases using recombinant PrP and scrapie-infected mouse neuroblastoma cells, an established in vitro model of prion disease. When recombinant PrP was incubated with PBS in the absence of HFIP for 24 h, PrP fibrillated and formed an unbranched linear structure (Fig. 1A (a)–(c), magnified images (d)–(f)).

Results

Conclusion