2004 Fiscal Year Final Research Report Summary
Development and pharmacological analysis of therapeutic drugs for conformation diseases and prion diseases
| Project/Area Number |
14207030
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Tohoku University (2003-2004)
Kyushu University (2002) |
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Principal Investigator |
DOH-URA Katsumi Tohoku University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (00263012)
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| Co-Investigator(Kenkyū-buntansha) |
IWAKI Toru Kyushu University, Graduate School of Medical Sciences, Professor, 大学院・医学研究院, 教授 (40221098)
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| Project Period (FY) |
2002 – 2004
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| Keywords | conformation disease / amyloid / prion / Aβ / prophylactic and therapeutic medicine / drug screening / pharmacology / in vivo assay |
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| Research Abstract |
This research was aimed to not only develop prophylactic and therapeutic drugs for any type of conformation diseases such as prion diseases, Alzheimer's disease and amyloidoses, but also clarify the pharmacology of the drugs acting on the abnormal conformation proteins.
Using three in-vitro assays, candidate chemicals were screened, and many potent candidates which were non-neurotoxic and effective to inhibit both the aggregation of each amyloidotic protein and the neurotoxicity. These included quinoline compounds, benzothiazole compounds, non-quinoline chelatirig chemicals, Congo red related chemicals, sulfated polysaccharides and so on.
The mechanism of action by the candidate chemicals on amyloidotic peptides derived from each of the amyloidotic proteins was examined by either surface plasmon resonance or circular dicroism. The results suggested that most of the chemicals could interact with a hydrophobic amino acid sequence of the core beta sheet structure in a hydrophobic pocket of
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the amyloidotic proteins. They also showed that strength of hydrophobic bonding by the chemicals was correlated with effectiveness in inhibiting the aggregation of the amyloidotic proteins but was not always correlated with effectiveness in inhibiting the neurotoxicity.
Several of the chemicals which penetrated into the brain were assayd in three types of conformation disease model mice. The results showed that compound A in per oral administration was safe and very effective as a prophylactic and therapeutic drug, and also compound MC in even one shot subcutaneous administration was much safer and the most beneficial in the prophylaxis and therapeutics. However, there were some ineffective chemicals in vivo which even easily penetrated into the brain and bound to the depositions composed of the abnormal conformation proteins. Several in-vitro and in-vivo experiments suggested that this inconsistency might be caused by conformational variety of the abnormal proteins and host factor(s).
The findings of the research indicate that the research for the development of conformation disease medicine is now ready for the next stage of translational research. Less
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