NR AOUO
AU Kawatake,S.; Doh-ura,K.; Murakami-Kubo,I.; Sakaguchi,S.; Iwaki,T.
TI Interaction of anti-prion chemicals with prion protein analyzed by surface plasmon resonance
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-74
PT Konferenz-Poster
AB
Prion diseases are fatal neurological disorders, and therapeutic interventions are recently vigorously studied. Many chemicals including antimalarial chemicals and amyloid dyes have been demonstrated to have anti-prion activity in vitro or in vivo, and Congo red is known to directly interact with PrPc. However, it is not clear whether the other anti-prion chemicals directly interact with PrPc. Thus, we made an analysis of binding affinity between recombinant PrP121-231 and anti-prion chemicals, such as quinacrine, chloroquine, Congo red, phthalocyanine tetrasulfonate, tetracycline and some other related chemicals by surface plasmon resonace. The affinity strength was compared with PrPsc inhibition dose (IC50) in scrapie-infected neuroblastoma (ScN2a) cells.
On the basis of affinity strength, the chemicals were classified into three groups as followed. Quinacrine and chloroquine had such low affinity with PrP121-231 that they showed very weak signal intensity and very rapid association and dissociation kinetics (Kd=0.1~1 mM). Congo red and phthalocyanine tetrasulfonate had higher affinity with PrP121-231 than quinacrine, and they showed strong signal intensity accompanied with slow dissociation kinetics (Kd<0.1 mM). Tetracycline did not show any binding signals with PrP121-231. The chemicals with binding affinity with PrP121-231 at Kd<1 mM were effective in inhibiting PrPsc formation in ScN2a cells in an IC50 dose less than 0.01 _M, and among these chemicals, affinity strength with PrP121-231 was well correlated to IC50 doses in ScN2a cells.
The findings suggest that chemicals of higher binding affinity with PrPc are more potent inhibitors of PrPsc formation. Screening of various chemicals of higher binding affinity with PrPc by surface plasmon resonance may be useful to find novel therapeutic candidates for prion diseases.
AD S. Kawatake, K. Doh-ura, I. Murakami-Kubo, T. Iwaki, Department of Neuropathology, Neurological Institute, Kyushu University, Japan; S. Sakaguchi, Department of Molecular Microbiology and Immunology, Nagasaki University, Japan
SP englisch
PO Deutschland