Astolfi, Andrea
Abstract:
A novel class of small molecule degraders targeting prion protein folding intermediate
Topic:
Decades of research efforts have conclusively provided overwhelming evidence that the cellular prion protein (PrPC) represents an optimal pharmaceutical target to tackle prion diseases, a set of fatal and incurable neurodegenerative disorders characterized by the conformational conversion of the physiological PrPC into a misfolded and infectious isoform referred to as PrP scrapie (PrPSc). Indeed, PrPC plays a key role in the disease etiology and knock-out experiments demonstrated that its therapeutic suppression can be considered safe. Over the years different strategies have been proposed to tackle this target based on traditional drug discovery approaches, such as the identification of small molecules able to promote the PrPC relocalization from cellular membrane to intracellular endosomes, as well as PrPC binders that prevent its conversion to PrPSc. However no therapy is yet available, and prion disease still represents a currently unmet medical need. Very recently, we have applied a novel drug discovery approach devoted to lowering PrPC levels by hampering a complete folding process. We refer to this strategy as Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT). The reconstruction of the PrP folding pathway through all-atoms MD simulation allowed the identification of a metastable intermediate of the PrP folding pathway characterized by a druggable pocket. Virtual screening of a commercial small molecule library resulted in the identification of thirteen potential binders, four of which capable of selectively lowering the load of PrP into the cellular membrane and promote its degradation. Additionally, one of these compounds inhibits prion replication in a dose-dependent fashion.
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