NR ATNK
AU Klingenstein,R.; Leliveld,S.R.; Korth,C.
TI Antiprion effects of quinacrine: potentiation and mechanism
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Human prions, risk of blood products, and therapy HUMAN-08
PT Konferenz-Poster
AB
Prion diseases are invariable fatal, neurodegenerative diseases caused by the
infectious agent consisting of PrPsc, a pathogenic, misfolded conformational isoform
of the normal prion protein (PrPc). So far, no pharmacotherapy exists that would halt the rapid progress of Creutzfeldt-Jakob disease and other prion diseases.
The identification of quinacrine as a lead compound of the group of heterocyclic antiprion compounds in a cell culture model of prion disease (ScN2a cells) has already led to several clinical trials aiming to confirm an antiprion effect in vivo. We were interested in identifying ways to potentiate quinacrine's antiprion effects and to reveal its mechanism of antiprion action.
Using the ScN2a model, we identified a strict structure-activity relationship of the heterocyclic group of iminodibenzyl derivatives that are also known as tricyclic antidepressants. Combination of these compounds and other clinically approved drugs with quinacrine had additive or synergistic effects on antiprion potency in ScN2a cells. As a mechanism of action of all heterocyclic antiprion compounds we could identify the destabilization of conversion-competent cell compartments.
Our data suggest that administration of a combination of clinically approved antiprion drugs including quinacrine may be superior to administration of quinacrine alone when treating CJD patients. Identification of a mechanism of action of heterocyclic antiprion compounds provides a rationale for further pharmacochemical development of these lead compounds.
*Supported by a grant from the Bundesministerium für Bildung und Forschung (BMBF), Germany
AD Ralf Klingenstein, Rutger Leliveld, Carsten Korth, University of Düsseldorf, Germany
SP englisch
PO Deutschland