NR ATGD
AU Kretzschmar,H.A.
TI In Search of Novel Antiprion Drugs
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-34
PT Konferenz-Vortrag
AB Systematic approaches to discover new anti-prion drugs have focused on interfering with the availability of PrPc and impeding the aggregation of PrP. Recent in vivo findings on the neuroprotective properties of PrPc in infarct models have cast some doubt on the feasibility of decreasing PrPc as a therapeutic strategy. We have focused on identifying drugs that impede the interaction of PrPc with PrPsc. Dual-color scanning for intensely fluorescent targets (SIFT), which has been used in the diagnosis of prion diseases, is presented here as a general technique to quantify and characterize prion protein aggregates. We have developed a high-throughput SIFT assay for the identification of drugs, which interfere with this interaction at the molecular level. Screening a library of 10,000 drug-like compounds yielded 256 primary hits, 80 of which were confirmed by dose-response curves. Among these, six compounds displayed an inhibitory effect on PrPsc propagation in scrapie-infected N2a cells. Four of these candidate drugs share an N'-benzylidene-benzohydrazide (NBB) core microstructure. Preliminary experiments with NBB in scrapie-infected mice have shown positive effects. Thus the combination of a high-throughput in-vitro assay with the established cell culture system provides a rapid and efficient method to identify new anti-prion drugs, which corroborates that interaction of PrPc and PrPsc is a crucial molecular step in the propagation of prions. In addition, SIFT-based screening may facilitate the search for drugs against other diseases linked to protein aggregation.
AD H.A.Kretzschmar, Ludwig-Maximilans-University Munich, Centre of Neuropathology and Prion Research, Feodor-Lynen-Str. 23, 81377 München, Germany
SP englisch
PO Deutschland