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Prion diseases involve misfolded and highly infectious aggregates of prion protein (PrPSc) which forms amyloid plaques leading to fatal neurodegeneration. PrPSc has an ability to act as the infectious seed which oligomerizes by recruiting the normal cellular forms, PrPC. This self-perpetuating nature of the prions has attracted the attention of a lot of researchers and extensive investigations have been done for enhanced understanding of the prion-like propagation of other amyloidogenic proteins. Previous attempts have been made to discover therapeutic agents/compounds against the infectious particle (PrPSc), which could effectively abrogate the pathogenic conditions, but none of them succeeded in effectively reducing the burden of this deadly pathogenic disorder. The absence of clinically proven therapeutics makes the discovery of effective remedial interventions a prime concern. Hence, there is a need to look for molecules which may help in stabilizing the actual conformation of natively folded prion protein (PrPC-like) by effectively interacting with it, and would eventually lead to the abrogation of growth of the infectious seeds thereby hampering the disease progression.
Herein this study, we report novel prion intervention by the virtually identified lead compounds which binds with moderate affinity to the recombinant protease resistant core of human prion protein (HuPrP) and inhibit its conversion into the highly neurotoxic forms.
In an attempt to identify potential inhibitors of HuPrP aggregation into amyloids, we employed virtual screening technique and obtained various natural compounds (polydatin, hesperdin, and ribavirin) from different compound libraries as the prospective candidates exhibiting potential binding with the active site of HuPrP. The modulating effects of these top hits were confirmed via in silico MD and REMD simulations technique. The detailed study using REMD simulations showed that these compounds prevent β-sheet transitions in the amyloidogenic, neurotoxic region of prion and induces antagonistic flexibilities. This was followed by experimental validation using an amalgamation of various biophysical techniques, surface plasmon resonance, high-end microscopic imaging, followed by cell-based evaluation to confirm the binding specificity and compelling anti-aggregating effects of the three identified compounds on prion protein. The combined results from these experiments showed that our lead compounds exhibit inhibitory effects on fibril formation along with having an ability to suppress conversion of HuPrP conformations into off-pathway oligomeric forms. These compounds ultimately lead to amelioration of neural toxicity of HuPrP oligomers by causing significant reduction in the cellular inhibition.
Collectively, our results affirm the importance of polydatin, ribavirin, and hesperidin in crippling the prion pathogenesis, thereby, making them as probable candidates for being used in anti-prion therapeutics. Moreover, these natural small molecules may serve as a structural scaffold for designing novel therapeutic agents targeting amyloidogenic transition in prions. Furthermore, this approach of prion intervention may also prove to be effective against other neurodegenerative disorders by reducing the amyloid forming ability of related proteins.
