Synthesis and in silico and in vitro evaluation of trimethoxy-benzamides designed as anti-prion derivatives

X-ray crystallographic fragment screening against the human prion protein

“…To our knowledge, these are the first binder with reported mechanism of interaction with PrP to be reported. Moreover, previous efforts to identify hot and warm spots in PrP structure identified a small hydrophobic close to where the fragment binds (KUWATA et al, 2007), on the other side of helix 3 (Figure 31), and to which anti-prion compounds, such as GN8, are known to interact (CONCEIÇÃO et al, 2019;YAMAGUCHI et al, 2019), thus suggesting that the fragment bind to an important region in the PrP structure. The GN8 anti-prion activity is attributed to a chaperone-like interaction, increasing the PrP stability and the proximity between GN8 and 4-pyrazolecarboxylate could be explored in merging approaches by linking through the loop 2.…”

“…Despite the absence of treatment for prion disease, many therapeutic approaches to treat the disease have been proposed and many compounds with anti-prion activities are known (ALTIERI et al, 2020;CONCEIÇÃO et al, 2019;IMBERDIS et al, 2016;MASHIMA et al, 2020). For instance, the reduction of PrP expression has an extremely strong proof of principle as a therapeutic strategy.…”