A Novel Approach to Preventing the PrPSc Induced Neurotoxicity Which Characterizes Creutzfeldt-Jakob Disease Through the Inhibition of Glypican-1
Year: 2024
Type: article
Abstract: Objective In this paper, our project focuses on a drug-based solution to Creutzfeldt-Jakob Disease, exploring a novel approach of targeting Glypican-1, found in the cellular pathway where PrPC changes. We propose the inhibition of the scaffolding protein GPC-1 through the ligand Monomethyl Auristatin F (MMAF) as a method of preventing the formation of infectious scrapie isoforms of the cellular prion protein (PrPSc). Competitive inhibition of GPC-1 will prevent the PrPSc induced neurotoxicity which characterizes CJD. Background Creutzfeldt-Jakob (CJD) disease is a rapid and invariably fatal disease for which no cure currently exists. It is characterized by aggregation of misfolded proteinaceous infectious particles (prions). In CJD the healthy cellular prion protein (PrPC) undergoes conformational changes, going from an α-helix-rich secondary structure to containing more β-sheets. These changes cause the protein to gain mechanisms of aggregation and become less prone to lysis. These qualities make CJD an aggressive disorder with devastating impacts. Design/Methods We have used advanced computational techniques to simulate drug delivery of MMAF as a therapy for Creutzfeldt Jakob disease. Docking run on the software HADDOCK (High Ambiguity Driven protein-protein DOCKing) was utilized to initially compare binding efficacies of both Glypican-1 and PrPc and then Glypican-1 and MMAF. Next, a 100 nanosecond simulation between Glypican-1 and MMAF was run on SiBioLead. Results were finally analyzed and visualized via BIOVIA discovery studio visualizer. Results MMAF had a HADDOCK score of 10.0 when docked to Glypican-1, while PrPC had a score of 32.9. This lower score indicates MMAF is a strong candidate for competitive inhibition of Glypican-1 in CJD patients. Along with this, we ran an advanced molecular dynamics simulation that revealed that MMAF sustained hydrogen bonds with Glypican-1, and had minimal fluctuation in the ligand Root-Mean-Square-Deviation (RMSD) indicating binding. Conclusions Our experiments therefore suggest that MMAF can effectively stop the flux of PrPSc aggregates.
Source: Neurology
Authors: Smriti Rajan, Sanjay Rajan
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: Horizon Therapeutics, EMD Serono
OpenAlex ID: W4403206928