1999 Fiscal Year Final Research Report Summary
Development of Anti-malarial Drug and it's Molecular Target
| Project/Area Number |
08281105
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas (A)
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| Allocation Type | Single-year Grants |
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| Research Institution | Okayama University |
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Principal Investigator |
WATAYA Yusuke Okayama University, Graduate School of Nature. Professor, 大学院・薬学研究科, 教授 (90127598)
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| Co-Investigator(Kenkyū-buntansha) |
KITA Kiyoshi The University of Tokyo, Graduate School of Mediciile, Professor, 大学院・医学系研究科, 教授 (90134444)
ITAI Akiko Kitazato Institute, Director, 部長研究員 (60012647)
MATSUDA Akira Hokkaido University, Graduate School of Pharmacy, Professor, 大学院・薬学研究科, 教授 (90157313)
SEKIMIZU Kazuhisa The Univ. of Tokyo, Graduate School of Pharmacy, Professor, 大学院・薬学系研究科, 教授 (90126095)
KIMURA Masatsugu Osaka City University, School of Medicine, Research Associate, 医学部, 助手 (60195378)
MORIYAMA Yoshiuori Okayama University, Graduate School of Nature, Professor (10150658)
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| Project Period (FY) |
1996 – 1999
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| Keywords | Malaria / Anti-malaria drug / Screening / antisense / tropical fever / protozoa / Plasmodium falciparum / target molecule |
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| Research Abstract |
The research project involves scientists from numerous research fields and has already contributed greately to the research of malaria by developing new antimalarial agents.
1) We are screening 4,635 samples containing natural products, organic compounds, microorganism-derived products, combinatorial bio-compounds and marine products that are alleged to have antimalarial activity. As the results, 165 compounds with high selective antimalarial activity (selective cytotoxicity is over 100) for Plasmodium falciparum were obtained using in vitro assay system. The study of in vitro and in vivo demonstrated that 1,2,6,7-tetraoxaspiro[7.11]nonadecane is the attractive prototype in a new class of inexpensive peroxide antimalarial drugs.
2) We have made a chimera-gene vector named CMC expressing a chimeric protein of P-ATPase (PfATP6 in P. falciparum) and chicken Ca-ATPase to demonstrate these functions essential for malaria parasites. PfATPase were expressed at the stage of trophozoites in P. fa
… More
lciparum.
3) We have identified a NSF homologue in Plasmodium falciparum (pfNSF) which is exported to extracellular space and localized with intraerythrocytic vesicles. The vesicular transport mechanism is involved in protein export to erythrocyte during intraerythrocytic development of malaria parasite.
4) We have isolated Ip subunit of Plasmodium succinate-ubiquinone reductase (complex II) in themitochondrial respiratory chains which is good targets for chemotherapy. Western blot using antibody against the recombinant Ip and northern analysis clearly showed that expression of parasite complex II is highest at late trophozoite/schizont stages of P. falciparum.
5) Phosphorothioate (PS) antisense (AS) oligonucleotides(ODNs) have widely been used as a tool to identify a role of a target protein. However, we tested several PSAS-ODNs and their sense ODNs against several enzymes in P. falciparum without significantly different effects. On the other hands, ODNs having phsphodiester (PO) bond, which are resistant to endo- and exo-nucleases, showed that AS-ODNs are more effective than their sense ODNs. Using this ODN, we found that succinate dehydrogenase was functionally active in P. falciparum and is a target enzyme to search anti-parasitic agents.
6) Our goal is to establish animal models for human malaria infection where one can evaluate candidates for anti-malaria drugs. We are also trying to understand molecular mechanisms for the invasion of the parasite into red blood cells. We already constructed mutant mice disrupting the gene encoding Duffy antigen by gene targeting technique.
7) A three-dimensional structure model of dihydrofolate reductase(DHFR) domain of P. falciparum DHFR-TS was predicted based on the X-ray structures of other species. It was used to design new inhibitors effective to cycloguanil-resistant FCR3 strain. As result, highly effective and selective inhibitors were developed. We also found new inhibitors with different skeletal stuructures from known DHFR inhibitors. Less
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