High-Throughput Screening of Compounds for Anti-Transmissible Spongiform Encephalopathy Activity Using Cell-Culture and Cell-Free Models and Infected Animals
Abstract
Transmissible spongiform encephalopathies (TSEs) are fatal untreatable neurodegenerative diseases associated with the accumulation of a disease-specific form of prion protein (prp(expSc)) in the brain. One approach to TSE therapeutics is the inhibition of PrP(exp Sc) accumulation. Indeed, many inhibitors of prp(exp sc) accumulation in scrapie-infected mouse neuroblastoma cells (ScN2a) also have anti-scrapie activity in rodents. To expedite the search for potential TSE therapeutics, we have developed a high-throughput screening assay for PrP(exp Sc) inhibitors using ScN2a cells in a 96 well format. A library of 2000 drugs and natural products was screened in ScN2a cells infected with RML (Chandler) or 22L scrapie strains. Seventeen had IC(sub 50) values of < 1 micronmeter against both strains. Several classes of compounds were represented in the 17 most potent inhibitors including naturally occurring polyphenols (e.g. tannic acid and tea extracts), phenothiazines, antihistamines, statins, and antimalarials. Several of the new PrP(exp Sc) inhibitors cross the blood-brain barrier and thus have potential to be effective after TSE infection reaches the brain. Initial -testing of inhibitors in transgenic mice was not effective, and this testing is described herein. Compounds were tested prior to ip inoculation and after ic inoculation.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA430509
Entities
People
- Byron Caughey
Organizations
- National Institutes of Health