Destabilization of the non-pathogenic, cellular prion-protein by a small molecular drug.
The presence of the normal cellular prion-protein (PrPc) is a prerequisite for the development of fatal, neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). We discovered a new biological activity of the well-known coumarin antibiotic novobiocin; the treatment of eukaryotic cells with novobiocin induces the rapid depletion of PrPc. This activity is shared by coumermycin A1, another coumarin with a related molecular structure. Novobiocin's effects on the prion-protein are time- and dose-dependent. No permanent damage to the treated cells was observed, which continue to proliferate after cessation of drug exposure. Most of the cellular proteins are unaffected by novobiocin treatment. Pretreatment with geldanamycin, an inhibitor of the aminoterminal ATPase of heat-shock protein 90 (Hsp90) partially antagonizes novobiocin's depletory activity. Concurrent treatment with the protease inhibitor chymostatin completely prevents PrPc loss. Here we show that the stability of the normal cellular prion-protein may be targeted pharmacologically. These findings open up a hitherto unknown avenue to the study of TSEs in general and may have therapeutic implications.
Ochel
Hans-Joachim
HJ
Clinic for Radiation Therapy, Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. hans-joachim.ochel@medizin.uni-magdeburg.de
Gademann
Günther
G
D016227:Benzoquinones; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004121:Dimethyl Sulfoxide; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic; D009675:Novobiocin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D018621:PrPC Proteins / Q000032:analysis / Q000737:chemistry / Q000187:drug effects*; D011809:Quinones / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009842:Oligopeptides; D018621:PrPC Proteins; D011809:Quinones; D015842:Serine Proteinase Inhibitors; D009675:Novobiocin; C002101:chymostatin; D004121:Dimethyl Sulfoxide; C001277:geldanamycin