Pharmacological inactivation of the prion protein by targeting a folding intermediate

Abstract

Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. These techniques allowed us to design a drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein levels by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP and identified four different small molecule ligands for this conformer, all capable of selectively lowering the load of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.

The Promise of Mutation Resistant Drugs for SARS-CoV-2 That Interdict in the Folding of the Spike Protein Receptor Binding Domain

“…The concepts presented in this paper are similar to earlier proposals to develop drugs that might be therapeutic by interfering with the folding process [21,22]. There has been a growing interest in the possibility of modulating the folding process through the employment of specific molecules, and theoretical and experimental results have been recently reported that support the view that targeting folding dynamics is a promising path for therapeutic development [23][24][25]. The main difference between the proposal presented here and other approaches is that the FITR strategy aims to interdict in the folding process while the protein is still completely unfolded [13].…”

Identification of Two Early Folding Stage Prion Non-Local Contacts Suggested to Serve as Key Steps in Directing the Final Fold to Be Either Native or Pathogenic

“…There are many factors that go into the discovery of an effective therapeutic drug, and this natural suggestion or those possibly derived from it would also need to meet the host of criteria involved. The search for therapeutic drugs for prion diseases is an active field [60,73,74], including molecules aimed against the late stages of the folding process [75].…”

Polygoni multiflori radix extracts inhibit SARS-CoV-2 pseudovirus entry in HEK293T cells and zebrafish larvae

“…(ii) Docking modulation was performed using the “Compute LeadIT Docking” mode in the FlexX algorithm; ten binding conformations for each ligand were generated. (iii) The binding energy (i.e., ∆G) and estimated HYDE affinity (KiHYDE) for each ligand pose were calculated using the “Assess Affinity with HYDE in SEESAR” mode in the HYDE rescoring function ( Spagnolli et al, 2021 ).…”