Prions are abnormal pathogens which can be transmissible and able to inducing misfolding of specific normal cellular proteins. Prion disease is a general term for a bunch of fatal and currently incurable neurodegenerative diseases that affect not only humans, but in addition wild and captive animals. These diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or “mad cow disease”), and chronic wasting disease (CWD) that affects deer, moose, and moose.

The major event in these diseases is the conversion of prion protein (PrP^C) from a standard shape right into a pathological structure (PrP^sc), which is toxic to neurons and might replicate by binding to untransformed PrP^C Particles. This ability to self-replicate makes these misfolded proteins infectious, which has enormous public health consequences.

In a latest study, scientists from Boston University Chobanian & Avedisian School of Medicine identified 10 compounds which can be able to scale back PrP^sc levels in infected cells and showed that essentially the most potent molecules could also prevent the toxicity seen with PrP^sc to cultured neurons.

“Interestingly, five of those molecules have a history of use in humans: rimcazole and haloperidol for the treatment of neuropsychiatric conditions, (+)-pentazocine for the treatment of neuropathic pain, and SA 4503 and ANAVEX2-73, that are in clinical development for the treatment of ischemic stroke and Alzheimer’s disease, respectively,” explained lead creator Dr. Robert CC Mercer, an instructor of biochemistry and cell biology at the college.

Scientists initially investigated the antiprion properties of those molecules because they were known to bind to sigma (σ) receptors₁R and σ₂R), which that they had reason to consider were involved in prion proliferation. Using gene knockout (CRISPR) technology, they determined that sigma receptors should not appropriate targets for these drugs for his or her antiprion properties.

Using Neuro2a (N2a) cells from an experimental model that had been infected with prions, these cells were then exposed to increasing concentrations of every drug and levels of PrP^sc they were determined. They then used CRISPR technology to “edit” σ₁R and σ₂R in order that they not encoded the protein, and this was found to don’t have any effect on the decline in PrP^sc levels observed with medications. This led them to conclude that σ₁R and σ₂R weren’t answerable for the antiprion effects of those drugs. They then tested the flexibility of those drugs to inhibit PrP^C to PrP^sc conversion and located that that they had no effect on these cell-free reactions, indicating that the consequences of those drugs were mediated by one other protein.

Scientists say prion diseases have enormous public health implications, from the protection of the blood supply to the correct decontamination of surgical instruments utilized in neurosurgery. “From a clinical standpoint, we consider that this study has revealed the antiprion properties of medication which have already been shown to be secure to be used in humans. Because of this, especially given the dearth of effective treatments for these diseases, these compounds might be repurposed to treat prion diseases,” said correspondent David A. Harris, M.D., the Edgar Minas Housepian Professor and chair of the college’s biochemistry and cell biology department.

These findings appear in an internet journal ACS Chemical Neuroscience.

Funding for this study was provided by National Institutes of Health Grant No. 5R01NS065244 awarded to David A. Harris. Robert CC Mercer is supported by grants from the Department of Defense (W81XWH-21-1-0141) and the Creutzfeldt-Jakob Disease Foundation.