Novel function of DNMT inhibitors to suppress prions

Abstract

The conversion of the normal cellular prion protein (PrPC) to the misfolded pathogenic scrapie prion protein (PrPSc) is the biochemical hallmark of prion replication. Various chemical compounds that inhibit this conformational conversion have been identified. Here, we present the anti-prion activity of SGI-1027 and its meta/meta analog (M/M), known as potent inhibitors of DNA methyltransferases (DNMTs). These compounds effectively decreased the level of PrPSc in cultured cells with permanent prion infection, irrespective of PrPC suppression at the transcriptional and translational levels, via DNMT inhibition. Furthermore, SGI-1027 prevented effective prion infection of the cells. In a PrP aggregation assay, both SGI-1027 and M/M blocked the formation of misfolded PrP aggregates, implying that binding of these compounds hinder the PrP conversion process. A series of binding and docking analyses demonstrated that both SGI-1027 and M/M directly interacted with the C-terminal globular domain of PrPC, but only SGI-1027 bound to a specific region of PrPC with high affinity, which correlates with its potent anti-prion efficacy. Therefore, SGI-1027 and related compounds represent potential anti-prion agents that operate through direct interaction with PrPC.