NR AORG
AU Caughey,B.W.; Kocisko,D.A.; Baron,G.S.; Speare,J.O.; Maxson,L.
TI Prion protein isoform interactions, inhibitors and TSE therapeutics
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-06
PT Konferenz-Vortrag
AB
We have studied the interactions between PrP-sen and PrPres (PrPsc) with the goal of understanding PrP conversion and disease propagation within the host. In recent experiments we have found that membrane associations of PrPres and PrP-sen strongly affect the conversion of PrP-sen to PrPres (J Biol Chem 2003;278(17):14883-92). In other studies we have found that mutations of helix 1 aspartate residues generate PrP-sen molecules that are several fold more efficiently converted than wildtype PrP-sen (J Biol Chem 2003;278(14):12522-9).
The development of new high-throughput assays for inhibitors of PrPres formation has allowed us to screen thousands of compounds for inhibition of PrPres formation in neuro 2a cells infected with the Chandler and 22L strains of scrapie. Most of the compounds tested from a 2000-compound library of approved drugs and natural products were not inhibitory. However, several new classes of inhibitors were identified that potently block PrPres formation without apparent cytotoxicity in both Chandler and 22L infected cells (J Virol, in press). Some of these inhibitors directly interfere with the PrP conversion reaction in cell-free conversion reactions, while others appear to have less direct mechanisms of action in intact cells. The development of a solid phase cell-free conversion reaction (Anal Biochem, in press) facilitiated the identification of direct inhibitors of PrP conversion. The best examples of these classes of inhibitors are being tested in scrapie-infected rodents for efficacy as prophylactic or therapeutic agents.
AD Byron Caughey, David A. Kocisko, Gerald S. Baron, Jonathon O. Speare, Laura Maxson, Laboratory of Persistent Viral Diseases, Rocky Mountain Labs, NIAID, NIH, USA
SP englisch
PO Deutschland