Effects of SGI-1027 on Formation and Elimination of PrP(Sc)in Prion-Infected Cells

Abstract

Recently, SGI-1027, a well-known inhibitor of DNA-methyl transferases (DNMTs), was reported to effectively reduce formation of pathogenic PrP(Sc)in prion-infected cells. Herein, we confirm the elimination of PrP(Sc)in chronic wasting disease (CWD) prion-infected neurons by SGI-1027, and pinpoint the binding region of human prion protein to SGI-1027. SGI-1027 is broadly functional against various prion disease types, including human prions. Previously, the inhibitory effects of SGI-1027 on DNMT function is well tested in various cell culture models. While neither treatment with a DNMTs enhancer S-adenosyl-L-methionine (SAM), nor with their inhibitor, 5-azacytidine, prevented PrP(Sc)propagation, SGI-1027 did. Our study suggest that the anti-prion effects of SGI-1027 are a result of its direct interaction with PrP (c), which effectively interferes with the pathogenic conformational change of PrP (c) to PrPSc. We conclude that SGI-1027 driven suppression of pathogenic PrP(Sc)is independent of DNMT.